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(DB_ID 140942) (text "The Tumor Necrosis Factor alpha (TNF-alpha) mediated apoptosis pathway has been implicated in the pathogenesis of a number of diseases including sepsis, diabetes, cancer, osteoporosis, multiple sclerosis, rheumatoid arthritis, and inflammatory bowel diseases. The TNF signaling network provides extensive cross talk between the apoptotic pathway, and the other NF-B, and JNK pathways that also emanate from TNF-R.")) ([GK_140943] of Person (_displayName "Stauber, GB") (DB_ID 140943) (initial "GB") (surname "Stauber")) ([GK_140944] of Person (_displayName "Chen, G") (DB_ID 140944) (initial "G") (surname "Chen")) ([GK_140945] of LiteratureReference (_displayName "Human tumor necrosis factor-alpha receptor. Purification by immunoaffinity chromatography and initial characterization.") (author [GK_140943] [GK_140940] [GK_140938]) (DB_ID 140945) (journal "J Biol Chem") (pages "19098-104") (pubMedIdentifier 2848815) (title "Human tumor necrosis factor-alpha receptor. 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(DB_ID 141083) (literatureReference [GK_140992]) (text "Tumor necrosis factor-related apoptosis-inducing ligand or Apo 2 ligand (TRAIL/Apo2L) is a member of the tumor necrosis factor (TNF) family. This group of apoptosis induction pathways all work through protein interactions mediated by the intracellular death domain (DD), encoded within the cytoplasmic domain of the receptor. TRAIL selectively induces apoptosis through its interaction with the Fas-associated death domain protein (FADD).")) 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Chemin des Boveressses 155
CH-1066 Epalinges
Switzerland") (DB_ID 157508) (name "University of Lausanne")) ([GK_158007] of Affiliation (_displayName "Cold Spring Harbor Laboratory") (address "1 Bungtown Road, Cold Spring Harbor, NY 11724") (DB_ID 158007) (name "Cold Spring Harbor Laboratory" "CSHL")) ([GK_159979] of GO_CellularComponent (_displayName "protein complex") (accession "0043234") (DB_ID 159979) (definition "Any macromolecular complex composed of two or more polypeptide subunits, which may or may not be identical. Protein complexes may have other associated non-protein prosthetic groups, such as nucleotides, metal ions or other small molecules.") (instanceOf [GK_258170]) (name "protein complex") (referenceDatabase [GK_1])) ([GK_159990] of GO_BiologicalProcess (_displayName "positive regulation of biological process") (accession "0048518") (DB_ID 159990) (definition "Any process that activates or increases the frequency, rate or extent of a biological process. Biological processes are regulated by many means; examples include the control of gene expression, protein modification or interaction with a protein or substrate molecule.") (instanceOf [GK_139810]) (name "positive regulation of biological process") (positivelyRegulate [GK_106]) (referenceDatabase [GK_1])) ([GK_160064] of GO_BiologicalProcess (_displayName "positive regulation of cellular process") (accession "0048522") (DB_ID 160064) (definition "Any process that activates or increases the frequency, rate or extent of a cellular process, any of those that are carried out at the cellular level, but are not necessarily restricted to a single cell. For example, cell communication occurs among more than one cell, but occurs at the cellular level.") 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(instanceOf [GK_160116] [GK_160291]) (name "positive regulation of hydrolase activity") (positivelyRegulate [GK_450]) (referenceDatabase [GK_1])) ([GK_160294] of GO_BiologicalProcess (_displayName "positive regulation of cysteine-type endopeptidase activity involved in apoptotic process") (accession "0043280") (componentOf [GK_2273]) (DB_ID 160294) (definition "Any process that activates or increases the activity of a cysteine-type endopeptidase involved in the apoptotic process.") (instanceOf [GK_160292] [GK_1996045]) (name "positive regulation of cysteine-type endopeptidase activity involved in apoptotic process") (positivelyRegulate [GK_2133460]) (referenceDatabase [GK_1])) ([GK_160483] of GO_CellularComponent (_displayName "extraorganismal space") (accession "0043245") (DB_ID 160483) (definition "The environmental space outside of an organism; this may be a host organism in the case of parasitic and symbiotic organisms.") (instanceOf [GK_258201]) (name "extraorganismal space") (referenceDatabase [GK_1])) ([GK_160565] of GO_BiologicalProcess (_displayName "positive regulation of apoptotic process") (accession "0043065") (DB_ID 160565) (definition "Any process that activates or increases the frequency, rate or extent of cell death by apoptotic process.") (instanceOf [GK_139812] [GK_160227]) (name "positive regulation of apoptotic process") (positivelyRegulate [GK_2273]) (referenceDatabase [GK_1])) ([GK_161217] of GO_CellularComponent (_displayName "death-inducing signaling complex") (accession "0031264") (DB_ID 161217) (definition "A protein complex formed by the association of signaling proteins with a death receptor upon ligand binding. The complex includes procaspases and death domain-containing proteins in addition to the ligand-bound receptor.") 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A peptide bond is a covalent bond formed when the carbon atom from the carboxyl group of one amino acid shares electrons with the nitrogen atom from the amino group of a second amino acid.") (ecNumber "3.4" "3.4" "3.4" "3.4" "3.4" "3.4" "3.4" "3.4" "3.4" "3.4" "3.4" "3.4" "3.4" "3.4" "3.4" "3.4" "3.4") (instanceOf [GK_450]) (name "peptidase activity") (referenceDatabase [GK_1])) ([GK_171090] of Person (_displayName "Soutar, AK") (DB_ID 171090) (firstname "Anne K") (initial "AK") (surname "Soutar")) ([GK_174719] of EntityWithAccessionedSequence (_displayName "[Hsa] perlecan [plasma membrane]") (compartment [GK_876]) (DB_ID 174719) (endCoordinate 4391) (name "perlecan" "HSPG2") (referenceEntity [GK_61584]) (species [GK_48887]) (stableIdentifier [GK_366563]) (startCoordinate 22)) ([GK_178760] of Summation (_displayName "Monomeric caspase-8 zymogens undergo dimerization and subseq...") (DB_ID 178760) (text "Monomeric caspase-8 zymogens undergo dimerization and subsequent conformational changes at the FASL:FAS Receptor Trimer:FADD:procaspase-8 receptor complex leading to the formation of the catalytically active form of procaspase-8.")) ([GK_178761] of Summation (_displayName "FASL (FAS antigen ligand) binds FAS receptor (CD95) (Brunner...") (DB_ID 178761) (literatureReference [GK_140513]) (text "FASL (FAS antigen ligand) binds FAS receptor (CD95) (Brunner et al. 1995). ")) ([GK_178762] of Summation (_displayName "FADD (FAS-associating death domain-containing) protein binds...") (DB_ID 178762) (literatureReference [GK_140495]) (text "FADD (FAS-associating death domain-containing) protein binds FASL:FAS receptor trimer through interaction of death domains of FADD and FAS (Boldin et al. 1995).")) ([GK_178763] of Summation (_displayName "FADD recruits caspase-10 precursor (pro-caspase-10) to FASL:...") (DB_ID 178763) (literatureReference [GK_141306] [GK_141314]) (text "FADD recruits caspase-10 precursor (pro-caspase-10) to FASL:FAS receptor trimer (Wang et al. 2001, Sprick et al. 2002). ")) ([GK_178764] of Summation (_displayName "Caspase-8 precursor (Pro-Caspase-8, also known as MACH) bind...") (DB_ID 178764) (literatureReference [GK_140941]) (text "Caspase-8 precursor (Pro-Caspase-8, also known as MACH) binds the complex of FADD and FASL:FAS receptor trimer (Boldin et al. 1996). ")) ([GK_178769] of Summation (_displayName "Caspase-8 zymogens are present in the cells as inactive mono...") (DB_ID 178769) (text "Caspase-8 zymogens are present in the cells as inactive monomers, containing a large N-terminal prodomain with two death effector domains (DED), and a C-terminal catalytic subunit composed of small and a large domains separated by a smaller linker region [Donepudi M et al 2003; Keller N et al 2009]. Dimerization is required for the caspase-8 activation [Donepudi M et al 2003]. Once dimerized, caspase-8 zymogen undergoes a series of autoproteolytic cleavage events at aspartic acid residues in their interdomain linker regions. A second cleavage event between the the N-terminal prodomain and the catalytic domain releases the active caspase from the activation complex into the cytosol. The resulting fully active enzyme is a homodimer of catalytic domains, where each domain is composed of a large p18 and a small p10 subunit [Keller N et al 2009; Oberst A et al 2010].")) ([GK_179238] of Summation (_displayName "TNF-alpha (tumor necrosis factor-alpha, TNF) binds TNF-RI (t...") (DB_ID 179238) (literatureReference [GK_140945]) (text "TNF-alpha (tumor necrosis factor-alpha, TNF) binds TNF-RI (tumor necrosis factor receptor superfamily member 1A, TNFRSF1A) (Stauber et al. 1988).")) ([GK_179239] of Summation (_displayName "Monomeric caspase-8 zymogens undergo dimerization and subseq...") (DB_ID 179239) (text "Monomeric caspase-8 zymogens undergo dimerization and subsequent conformational changes at the TRADD:TRAF2:RIP1:FADD:Capase-8 receptor complex leading to the formation of the catalytically active form of procaspase-8.")) ([GK_179240] of Summation (_displayName "Caspase-8-precursor (pro-caspase-8) binds TRAF2:TRADD:RIP1:F...") (DB_ID 179240) (literatureReference [GK_140979]) (text "Caspase-8-precursor (pro-caspase-8) binds TRAF2:TRADD:RIP1:FADD complex (Micheau and Tschopp, 2003). ")) ([GK_179243] of Summation (_displayName "TRAIL (TNF-related apoptosis-inducing ligand) binds TRAIL re...") (DB_ID 179243) (literatureReference [GK_141147]) (text "TRAIL (TNF-related apoptosis-inducing ligand) binds TRAIL receptor-2 (TNFRSF10B) (Wiley et al. 1995). ")) ([GK_179244] of Summation (_displayName "Monomeric caspase-8 zymogens undergo dimerization and subseq...") (DB_ID 179244) (text "Monomeric caspase-8 zymogens undergo dimerization and subsequent conformational changes at the TRAIL:TRAIL receptor-2:FADD receptor complex leading to the formation of the catalytically active form of procaspase-8.")) ([GK_179245] of Summation (_displayName "The trimeric complex of TRAIL and TRAIL receptor-2 (TRAIL:TR...") (DB_ID 179245) (literatureReference [GK_141128]) (text "The trimeric complex of TRAIL and TRAIL receptor-2 (TRAIL:TRAIL receptor-2) binds FADD (Sprick et al. 2000).")) ([GK_179246] of Summation (_displayName "Caspase-10 precursor is recruited to the TRAIL:TRAIL recepto...") (DB_ID 179246) (literatureReference [GK_141306] [GK_141314]) (text "Caspase-10 precursor is recruited to the TRAIL:TRAIL receptor-2:FADD complex (Sprick et al. 2002) through interaction of death effector domains of caspase-10 and FADD (Wang et al. 2001). ")) ([GK_179247] of Summation (_displayName "FADD recruits caspase-8 precursor to trimeric complex of TRA...") (DB_ID 179247) (literatureReference [GK_141128]) (text "FADD recruits caspase-8 precursor to trimeric complex of TRAIL and TRAIL receptor 2 (Sprick et al. 2000).")) ([GK_179272] of Summation (_displayName "The complex of FASL (FAS antigen ligand) and FAS receptor (C...") (DB_ID 179272) (literatureReference [GK_140505]) (text "The complex of FASL (FAS antigen ligand) and FAS receptor (CD95) trimerizes (Kischkel et al. 1995).")) ([GK_179273] of Summation (_displayName "The complex of TRAIL and TRAIL receptor-2 trimerizes (Sprick...") (DB_ID 179273) (literatureReference [GK_141128]) (text "The complex of TRAIL and TRAIL receptor-2 trimerizes (Sprick et al. 2000). ")) ([GK_1793] of GO_MolecularFunction (_displayName "endopeptidase activity") (accession "0004175") (DB_ID 1793) (definition "Catalysis of the hydrolysis of internal, alpha-peptide bonds in a polypeptide chain.") 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(DB_ID 213088) (text "Caspase-8 is synthesized as zymogen (procaspase-8) and is formed from procaspase-8 as a cleavage product. However, the cleavage itself appears not to be sufficient for the formation of an active caspase-8. Only the coordinated dimerization and cleavage of the zymogen produce efficient activation in vitro and apoptosis in cellular systems [Boatright KM and Salvesen GS 2003; Keller N et al 2010; Oberst A et al 2010].

The caspase-8 zymogens are present in the cells as inactive monomers, which are recruited to the death-inducing signaling complex (DISC) by homophilic interactions with the DED domain of FADD. The monomeric zymogens undergo dimerization and the subsequent conformational changes at the receptor complex, which results in the formation of catalytically active form of procaspase-8.[Boatright KM et al 2003; Donepudi M et al 2003; Keller N et al 2010; Oberst A et al 2010].")) ([GK_213104] of Summation (_displayName "Procaspase-8 monomers undergo dimerization. The dimerization...") (DB_ID 213104) (text "Procaspase-8 monomers undergo dimerization. The dimerization event occurs at death-inducing signaling complex (DISC) and results in a reposition of the procaspase-8 inter-subunit linker to become accessible for intermolecular processing by the associated procaspase-8 molecule [Keller N et al 2010; Oberst A et al 2010].")) ([GK_2133460] of GO_MolecularFunction (_displayName "cysteine-type endopeptidase activity involved in apoptotic process") (accession "0097153") (componentOf [GK_2273]) (DB_ID 2133460) (definition "Catalysis of the hydrolysis of internal, alpha-peptide bonds in a polypeptide chain by a mechanism in which the sulfhydryl group of a cysteine residue at the active center acts as a nucleophile, and contributing to the apoptotic process.") (instanceOf [GK_4344]) (name "cysteine-type endopeptidase activity involved in apoptotic process") (referenceDatabase [GK_1])) ([GK_2133509] of GO_BiologicalProcess (_displayName "activation of cysteine-type endopeptidase activity") (accession "0097202") (DB_ID 2133509) (definition "Any process that initiates the activity of the inactive enzyme cysteine-type endopeptidase.") 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The process ends when the cell has died. The process is divided into a signaling pathway phase, and an execution phase, which is triggered by the former.") (instanceOf [GK_2274]) (name "apoptotic process") (referenceDatabase [GK_1])) ([GK_2274] of GO_BiologicalProcess (_displayName "programmed cell death") (accession "0012501") (DB_ID 2274) (definition "A process which begins when a cell receives an internal or external signal and activates a series of biochemical events (signaling pathway). The process ends with the death of the cell.") (instanceOf [GK_2275]) (name "programmed cell death") (referenceDatabase [GK_1])) ([GK_2275] of GO_BiologicalProcess (_displayName "cell death") (accession "0008219") (DB_ID 2275) (definition "Any biological process that results in permanent cessation of all vital functions of a cell. A cell should be considered dead when any one of the following molecular or morphological criteria is met: (1) the cell has lost the integrity of its plasma membrane; (2) the cell, including its nucleus, has undergone complete fragmentation into discrete bodies (frequently referred to as \"apoptotic bodies\"); and/or (3) its corpse (or its fragments) have been engulfed by an adjacent cell in vivo.") (instanceOf [GK_2276] [GK_3132308]) (name "cell death") (referenceDatabase [GK_1])) ([GK_2276] of GO_BiologicalProcess (_displayName "death") (accession "0016265") (DB_ID 2276) (definition "A permanent cessation of all vital functions: the end of life; can be applied to a whole organism or to a part of an organism.") (instanceOf [GK_2587987]) (name "death") (referenceDatabase [GK_1])) ([GK_231418] of ReferenceGeneProduct (_displayName "[Hsa] UniProt:Q6FI13 HIST2H2AA3 recommendedName: Histone H2A type 2-A alternativeName: Histone H2A.2 alternativeName: Histone H2A/o ") (checksum "1") (comment "FUNCTION Core component of nucleosome. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling.SUBUNIT The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA.PTM Deiminated on Arg-4 in granulocytes upon calcium entry.PTM Phosphorylation on Ser-2 is enhanced during mitosis. Phosphorylation on Ser-2 by RPS6KA5/MSK1 directly represses transcription. Acetylation of H3 inhibits Ser-2 phosphorylation by RPS6KA5/MSK1.SIMILARITY Belongs to the histone H2A family.") 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May be incorporated into a proportion of nucleosomes, replacing one or more H2A molecules.MISCELLANEOUS In contrast to other H2A histones, it does not contain the conserved residues that are the target of post-translational modifications.SIMILARITY Belongs to the histone H2A family.") (DB_ID 231427) (description "recommendedName: Histone H2A-Bbd type 1 alternativeName: H2A Barr body-deficient shortName:H2A.Bbd alternativeName: H2A Barr body-deficient shortName:H2A.Bbd ") (geneName "H2AFB1") (identifier "P0C5Y9") (isSequenceChanged TRUE) (keyword "Chromosome" "Complete proteome" "DNA-binding" "Nucleosome core" "Nucleus") (name "H2AFB1") (referenceDatabase [GK_2]) (secondaryIdentifier "H2AB1_HUMAN" "P98176" "Q5TZB2" "Q6FG78" "Q96PR7") (sequenceLength 115) (species [GK_48887])) ([GK_231437] of ReferenceGeneProduct (_displayName "[Hsa] UniProt:P0C0S5 H2AFZ recommendedName: Histone H2A.Z shortName:H2A/z ") (checksum "1") (comment "PTM Monoubiquitination of Lys-122 gives a specific tag for epigenetic transcriptional repression.SIMILARITY Belongs to the histone H2A family.") (DB_ID 231437) (description "recommendedName: Histone H2A.Z shortName:H2A/z ") (geneName "H2AFZ" "H2AZ") (identifier "P0C0S5") (isSequenceChanged TRUE) (keyword "3D-structure" "Acetylation" "Chromosome" "Complete proteome" "DNA-binding" "Isopeptide bond" "Nucleosome core" "Nucleus" "Ubl conjugation") (name "H2AFZ") (referenceDatabase [GK_2]) (secondaryIdentifier "H2AZ_HUMAN" "B2RD56" "P17317" "Q6I9U0") (sequenceLength 128) (species [GK_48887])) ([GK_23175] of GO_BiologicalProcess (_displayName "activation of cysteine-type endopeptidase activity involved in apoptotic process") (accession "0006919") (componentOf [GK_2273]) (DB_ID 23175) (definition "Any process that initiates the activity of the inactive enzyme cysteine-type endopeptidase in the context of an apoptotic process.") (instanceOf [GK_160294] [GK_2133509]) (name "activation of cysteine-type endopeptidase activity involved in apoptotic process") (referenceDatabase [GK_1])) ([GK_240941] of ReferenceGeneProduct (_displayName "[Hsa] UniProt:A1E959 ODAM recommendedName: Odontogenic ameloblast-associated protein alternativeName: Apin ") (checksum "1") (comment "FUNCTION Tooth-associated epithelia protein that probably plays a role in odontogenesis, the complex process that results in the initiation and generation of the tooth. May be incorporated in the enamel matrix at the end of mineralization process.MISCELLANEOUS ODAM protein is the unique constituent of calcifying epithelial odontogenic tumors (CEOTs), also known as Pindborg tumors. CEOTs are benign but locally aggressive pathologic entities arising mainly in the mandible and commonly associated with an unerupted or embedded tooth. They are characterized by the presence of squamous-cell proliferation, calcification, and, notably, amyloid deposits.SIMILARITY Belongs to the ODAM family.") (DB_ID 240941) (description "recommendedName: Odontogenic ameloblast-associated protein alternativeName: Apin ") (geneName "ODAM" "APIN") (identifier "A1E959") (isSequenceChanged TRUE) (keyword "Biomineralization" "Complete proteome" "Glycoprotein" "Polymorphism" "Secreted" "Signal") (name "ODAM") (referenceDatabase [GK_2]) (secondaryIdentifier "ODAM_HUMAN" "Q8WWE5" "Q9NWZ9") (sequenceLength 279) (species [GK_48887])) ([GK_2534135] of Person (_displayName "Salvesen, G S") (DB_ID 2534135) (firstname "G S") (initial "GS") (surname "Salvesen")) ([GK_25446] of GO_BiologicalProcess (_displayName "induction of apoptosis by extracellular signals") (accession "0008624") (DB_ID 25446) (definition "Any process induced by extracellular signals that directly activates any of the steps required for cell death by apoptosis.") (instanceOf [GK_6542]) (name "induction of apoptosis by extracellular signals") (referenceDatabase [GK_1])) ([GK_25482] of GO_BiologicalProcess (_displayName "activation of pro-apoptotic gene products") (accession "0008633") (componentOf [GK_2273]) (DB_ID 25482) (definition "The conversion of proteins that induce or sustain apoptosis to an active form.") (instanceOf [GK_160565]) (name "activation of pro-apoptotic gene products") (referenceDatabase [GK_1])) ([GK_2562543] of Person (_displayName "Heinrikson, R L") (DB_ID 2562543) (firstname "R L") (initial "RL") (surname "Heinrikson")) ([GK_2562547] of Person (_displayName "Mildner, A M") (DB_ID 2562547) (firstname "A M") (initial "AM") (surname "Mildner")) ([GK_2562548] of Person (_displayName "MacFarlane, Marion") (DB_ID 2562548) (firstname "Marion") (initial "M") (surname "MacFarlane")) ([GK_2562550] of Complex (_displayName "[Hsa] active caspase-8 [cytosol]") (compartment [GK_70101]) (DB_ID 2562550) (hasComponent [GK_139950] [GK_139950]) (isChimeric FALSE) (literatureReference [GK_2562575] [GK_2562554]) (name "active caspase-8 ") (species [GK_48887])) ([GK_2562552] of Person (_displayName "Tomasselli, A G") (DB_ID 2562552) (firstname "A G") (initial "AG") (surname "Tomasselli")) ([GK_2562554] of LiteratureReference (_displayName "The three-dimensional structure of caspase-8: an initiator enzyme in apoptosis") (author [GK_2562561] [GK_2562555] [GK_2562588] [GK_2562590] [GK_2562576] [GK_2562572] [GK_2562557] [GK_2562587]) (DB_ID 2562554) (journal "Structure") (pages "1125-33") (pubMedIdentifier 10508784) (title "The three-dimensional structure of caspase-8: an initiator enzyme in apoptosis") (volume 7) (year 1999)) ([GK_2562555] of Person (_displayName "Kodandapani, L") (DB_ID 2562555) (firstname "L") (initial "L") (surname "Kodandapani")) ([GK_2562557] of Person (_displayName "Tomaselli, K J") (DB_ID 2562557) (firstname "K J") (initial "KJ") (surname "Tomaselli")) ([GK_2562560] of Person (_displayName "Cain, Kelvin") (DB_ID 2562560) (firstname "Kelvin") (initial "K") (surname "Cain")) ([GK_2562561] of Person (_displayName "Blanchard, H") (DB_ID 2562561) (firstname "H") (initial "H") (surname "Blanchard")) ([GK_2562565] of Person (_displayName "Watt, W") (DB_ID 2562565) (firstname "W") (initial "W") (surname "Watt")) ([GK_2562569] of Person (_displayName "Watenpaugh, K D") (DB_ID 2562569) (firstname "K D") (initial "KD") (surname "Watenpaugh")) ([GK_2562572] of Person (_displayName "Wu, J C") (DB_ID 2562572) (firstname "J C") (initial "JC") (surname "Wu")) ([GK_2562575] of LiteratureReference (_displayName "The atomic-resolution structure of human caspase-8, a key activator of apoptosis") (author [GK_2562565] [GK_2562584] [GK_2562547] [GK_2562543] [GK_2562552] [GK_2562569]) (DB_ID 2562575) (journal "Structure") (pages "1135-43") (pubMedIdentifier 10508785) (title "The atomic-resolution structure of human caspase-8, a key activator of apoptosis") (volume 7) (year 1999)) ([GK_2562576] of Person (_displayName "Krebs, J F") (DB_ID 2562576) (firstname "J F") (initial "JF") (surname "Krebs")) ([GK_2562584] of Person (_displayName "Koeplinger, K A") (DB_ID 2562584) (firstname "K A") (initial "KA") (surname "Koeplinger")) ([GK_2562587] of Person (_displayName "Grütter, M G") (DB_ID 2562587) (firstname "M G") (initial "MG") (surname "Grütter")) ([GK_2562588] of Person (_displayName "Mittl, P R") (DB_ID 2562588) (firstname "P R") (initial "PR") (surname "Mittl")) ([GK_2562590] of Person (_displayName "Marco, S D") (DB_ID 2562590) (firstname "S D") (initial "SD") (surname "Marco")) ([GK_258123] of GO_BiologicalProcess (_displayName "biological regulation") (accession "0065007") (DB_ID 258123) (definition "Any process that modulates a measurable attribute of any biological process, quality or function.") (instanceOf [GK_106]) (name "biological regulation") (referenceDatabase [GK_1])) ([GK_258147] of GO_CellularComponent (_displayName "cell part") (accession "0044464") (componentOf [GK_356]) (DB_ID 258147) (definition "Any constituent part of a cell, the basic structural and functional unit of all organisms.") (instanceOf [GK_357]) (name "cell part") (referenceDatabase [GK_1])) ([GK_258148] of GO_CellularComponent (_displayName "intracellular part") (accession "0044424") (componentOf [GK_354]) (DB_ID 258148) (definition "Any constituent part of the living contents of a cell; the matter contained within (but not including) the plasma membrane, usually taken to exclude large vacuoles and masses of secretory or ingested material. In eukaryotes it includes the nucleus and cytoplasm.") (instanceOf [GK_258147]) (name "intracellular part") (referenceDatabase [GK_1])) ([GK_258154] of GO_CellularComponent (_displayName "membrane part") (accession "0044425") (componentOf [GK_383187]) (DB_ID 258154) (definition "Any constituent part of a membrane, a double layer of lipid molecules that encloses all cells, and, in eukaryotes, many organelles; may be a single or double lipid bilayer; also includes associated proteins.") (instanceOf [GK_357]) (name "membrane part") (referenceDatabase [GK_1])) ([GK_258155] of GO_CellularComponent (_displayName "plasma membrane part") (accession "0044459") (componentOf [GK_876]) (DB_ID 258155) (definition "Any constituent part of the plasma membrane, the membrane surrounding a cell that separates the cell from its external environment. It consists of a phospholipid bilayer and associated proteins.") (instanceOf [GK_258154] [GK_258147]) (name "plasma membrane part") (referenceDatabase [GK_1])) ([GK_258163] of GO_CellularComponent (_displayName "cytoplasmic part") (accession "0044444") (componentOf [GK_459]) (DB_ID 258163) (definition "Any constituent part of the cytoplasm, all of the contents of a cell excluding the plasma membrane and nucleus, but including other subcellular structures.") (instanceOf [GK_258148]) (name "cytoplasmic part") (referenceDatabase [GK_1])) ([GK_258170] of GO_CellularComponent (_displayName "macromolecular complex") (accession "0032991") (DB_ID 258170) (definition "A stable assembly of two or more macromolecules, i.e. proteins, nucleic acids, carbohydrates or lipids, in which the constituent parts function together.") (instanceOf [GK_357]) (name "macromolecular complex") (referenceDatabase [GK_1])) ([GK_258201] of GO_CellularComponent (_displayName "extracellular region part") (accession "0044421") (componentOf [GK_984]) (DB_ID 258201) (definition "Any constituent part of the extracellular region, the space external to the outermost structure of a cell. For cells without external protective or external encapsulating structures this refers to space outside of the plasma membrane. This term covers constituent parts of the host cell environment outside an intracellular parasite.") (instanceOf [GK_357]) (name "extracellular region part") (referenceDatabase [GK_1])) ([GK_258234] of GO_BiologicalProcess (_displayName "regulation of molecular function") (accession "0065009") (DB_ID 258234) (definition "Any process that modulates the frequency, rate or extent of a molecular function, an elemental biological activity occurring at the molecular level, such as catalysis or binding.") (instanceOf [GK_258123]) (name "regulation of molecular function") (referenceDatabase [GK_1]) (regulate [GK_43])) ([GK_2584552] of Person (_displayName "Wang, Xiaodong") (DB_ID 2584552) (firstname "Xiaodong") (initial "X") (surname "Wang")) ([GK_2584570] of Person (_displayName "Grütter, Markus G") (DB_ID 2584570) (firstname "Markus G") (initial "MG") (surname "Grütter")) ([GK_2584571] of Person (_displayName "Briand, Christophe") (DB_ID 2584571) (firstname "Christophe") (initial "C") (surname "Briand")) ([GK_2584573] of LiteratureReference (_displayName "Insights into the regulatory mechanism for caspase-8 activation") (author [GK_2584575] [GK_2584574] [GK_2584571] [GK_2584570]) (DB_ID 2584573) (journal "Mol. Cell") (pages "543-9") (pubMedIdentifier 12620240) (title "Insights into the regulatory mechanism for caspase-8 activation") (volume 11) (year 2003)) ([GK_2584574] of Person (_displayName "Mac Sweeney, Aengus") (DB_ID 2584574) (firstname "Aengus") (initial "A") (surname "Mac Sweeney")) ([GK_2584575] of Person (_displayName "Donepudi, Mrudula") (DB_ID 2584575) (firstname "Mrudula") (initial "M") (surname "Donepudi")) ([GK_2587987] of GO_BiologicalProcess (_displayName "single-organism process") (accession "0044699") (DB_ID 2587987) (definition "A biological process that involves only one organism.") (instanceOf [GK_106]) (name "single-organism process") (referenceDatabase [GK_1])) ([GK_258858] of GO_BiologicalProcess (_displayName "regulation of peptidase activity") (accession "0052547") (DB_ID 258858) (definition "Any process that modulates the frequency, rate or extent of peptidase activity, the hydrolysis of peptide bonds within proteins.") (instanceOf [GK_160291]) (name "regulation of peptidase activity") (referenceDatabase [GK_1]) (regulate [GK_1687])) ([GK_258859] of GO_BiologicalProcess (_displayName "regulation of endopeptidase activity") (accession "0052548") (DB_ID 258859) (definition "Any process that modulates the frequency, rate or extent of endopeptidase activity, the endohydrolysis of peptide bonds within proteins.") (instanceOf [GK_258858]) (name "regulation of endopeptidase activity") (referenceDatabase [GK_1]) (regulate [GK_1793])) ([GK_259431] of GO_CellularComponent (_displayName "host cell") (accession "0043657") (componentOf [GK_6486]) (DB_ID 259431) (definition "A cell within a host organism. Includes the host plasma membrane and any external encapsulating structures such as the host cell wall and cell envelope.") (instanceOf [GK_1470062]) (name "host cell") (referenceDatabase [GK_1])) ([GK_259432] of GO_CellularComponent (_displayName "host cell part") (accession "0033643") (componentOf [GK_259431]) (DB_ID 259432) (definition "Any constituent part of a host cell. The host is defined as the larger of the organisms involved in a symbiotic interaction.") (instanceOf [GK_447577]) (name "host cell part") (referenceDatabase [GK_1])) ([GK_259433] of GO_CellularComponent (_displayName "intracellular region of host") (accession "0043656") (DB_ID 259433) (definition "That space within the plasma membrane of a host cell.") (instanceOf [GK_259432]) (name "intracellular region of host") (referenceDatabase [GK_1])) ([GK_259434] of GO_CellularComponent (_displayName "host intracellular part") (accession "0033646") (componentOf [GK_259433]) (DB_ID 259434) (definition "Any constituent part of the living contents of a host cell; the matter contained within (but not including) the plasma membrane, usually taken to exclude large vacuoles and masses of secretory or ingested material. In eukaryotes it includes the nucleus and cytoplasm. The host is defined as the larger of the organisms involved in a symbiotic interaction.") (instanceOf [GK_259432]) (name "host intracellular part") (referenceDatabase [GK_1])) ([GK_259437] of GO_CellularComponent (_displayName "host cell cytoplasm part") (accession "0033655") (componentOf [GK_80155]) (DB_ID 259437) (definition "Any constituent part of the host cell cytoplasm, all of the contents of a cell excluding the plasma membrane and nucleus, but including other subcellular structures. The host is defined as the larger of the organisms involved in a symbiotic interaction.") (instanceOf [GK_259434]) (name "host cell cytoplasm part") (referenceDatabase [GK_1])) ([GK_2594924] of InstanceEdit (_displayName "Gillespie, ME, 2012-11-19") (author [GK_73681]) (dateTime "2012-11-19 14:31:40") (DB_ID 2594924)) ([GK_264348] of Person (_displayName "Steiner, DF") (DB_ID 264348) (initial "DF") (surname "Steiner")) ([GK_264874] of ModifiedResidue (_displayName "half cystine at 109") (coordinate 109) (DB_ID 264874) (psiMod [GK_448182]) (referenceSequence [GK_57415])) ([GK_264928] of ModifiedResidue (_displayName "half cystine at 95") (coordinate 95) (DB_ID 264928) (psiMod [GK_448182]) (referenceSequence [GK_57415])) ([GK_264936] of ModifiedResidue (_displayName "half cystine at 96") (coordinate 96) (DB_ID 264936) (psiMod [GK_448182]) (referenceSequence [GK_57415])) ([GK_265017] of ModifiedResidue (_displayName "half cystine at 43") (coordinate 43) (DB_ID 265017) (psiMod [GK_448182]) (referenceSequence [GK_57415])) ([GK_265035] of ModifiedResidue (_displayName "half cystine at 100") (coordinate 100) (DB_ID 265035) (psiMod [GK_448182]) (referenceSequence [GK_57415])) ([GK_265094] of ModifiedResidue (_displayName "half cystine at 31") (coordinate 31) (DB_ID 265094) (psiMod [GK_448182]) (referenceSequence [GK_57415])) ([GK_265170] of EntityWithAccessionedSequence (_displayName "[Hsa] Insulin A Chain [extracellular region]") (compartment [GK_984]) (DB_ID 265170) (endCoordinate 110) (hasModifiedResidue [GK_265035] [GK_264874] [GK_264928] [GK_264936]) (name "Insulin A Chain") (referenceEntity [GK_57415]) (species [GK_48887]) (stableIdentifier [GK_387943]) (startCoordinate 90)) ([GK_2671784] of EntityWithAccessionedSequence (_displayName "[Vvi] SPI-2 [cytosol]") (compartment [GK_70101]) (DB_ID 2671784) (endCoordinate 345) (goCellularComponent [GK_436407]) (name "SPI-2" "Serine proteinase inhibitor 2" "B13R") (referenceEntity [GK_2671799]) (species [GK_2671785]) (startCoordinate 1)) ([GK_2671785] of Species (_displayName "Vaccinia virus") (DB_ID 2671785) (name "Vaccinia virus")) ([GK_2671786] of EntityWithAccessionedSequence (_displayName "[Cvi] Serine proteinase inhibitor 2 [cytosol]") (compartment [GK_70101]) (DB_ID 2671786) (endCoordinate 341) (goCellularComponent [GK_436407]) (name "Serine proteinase inhibitor 2" "Serpin-2" "CRMA") (referenceEntity [GK_2671797]) (species [GK_2671792]) (startCoordinate 1)) ([GK_2671792] of Species (_displayName "Cowpox virus") (DB_ID 2671792) (name "Cowpox virus")) ([GK_2671797] of ReferenceGeneProduct (_displayName "[Cvi] UniProt:P07385 CRMA recommendedName: Serine proteinase inhibitor 2 shortName:Serp-2 shortName:Serpin-2 alternativeName: Cytokine response modifier protein A alternativeName: Hemorrhage-inducing 38 kDa protein alternativeName: ICE inhibitor ") (checksum "25AE4E0CB123E172") (comment "FUNCTION Specific and potent inhibitor of the interleukin-1-beta converting enzyme (ICE) thereby suppressing an interleukin-1 beta response to infection. The inhibition of ICE by crmA is an example of a \"cross-class\" interaction, in which a serpin inhibits a non-serine proteinase. Also inhibits granzyme B.SIMILARITY Belongs to the serpin family. Poxviruses subfamily.") (DB_ID 2671797) (description "recommendedName: Serine proteinase inhibitor 2 shortName:Serp-2 shortName:Serpin-2 alternativeName: Cytokine response modifier protein A alternativeName: Hemorrhage-inducing 38 kDa protein alternativeName: ICE inhibitor ") (geneName "CRMA" "SPI-2" "CPXV207") (identifier "P07385") (isSequenceChanged FALSE) (keyword "3D-structure" "Host cytoplasm" "Host-virus interaction" "Inhibition of host caspases by virus" "Modulation of host cell apoptosis by virus" "Protease inhibitor" "Thiol protease inhibitor") (name "CRMA") (referenceDatabase [GK_2]) (secondaryIdentifier "SPI2_CWPXB") (sequenceLength 341) (species [GK_2671792])) ([GK_2671799] of ReferenceGeneProduct (_displayName "[Vvi] UniProt:P15059 SPI-2 recommendedName: Serine proteinase inhibitor 2 shortName:Serp-2 shortName:Serpin-2 ") (checksum "8A067A10B803F5EF") (comment "FUNCTION Inhibits the proteolytic activity of interleukin 1-beta converting enzyme (ICE) and ICE-like enzymes. Can also block apoptosis through host tumor necrosis factor (TNF) receptor.INDUCTION Expressed in the early phase of the viral replicative cycle.SIMILARITY Belongs to the serpin family. Poxviruses subfamily.") (DB_ID 2671799) (description "recommendedName: Serine proteinase inhibitor 2 shortName:Serp-2 shortName:Serpin-2 ") (geneName "SPI-2" "VACWR195" "B13R") (identifier "P15059") (isSequenceChanged FALSE) (keyword "Complete proteome" "Early protein" "Host cytoplasm" "Host-virus interaction" "Inhibition of host caspases by virus" "Modulation of host cell apoptosis by virus" "Protease inhibitor" "Reference proteome" "Serine protease inhibitor") (name "SPI-2") (referenceDatabase [GK_2]) (secondaryIdentifier "SPI2_VACCW" "Q76ZL0") (sequenceLength 345) (species [GK_2671785])) ([GK_2671811] of Complex (_displayName "[Hsa] FASL:FAS receptor trimer:FADD:procaspase-8-dimer [plasma membrane]") (compartment [GK_876]) (DB_ID 2671811) (hasComponent [GK_43124] [GK_2671817]) (literatureReference [GK_2562554]) (name "FASL:FAS receptor trimer:FADD:procaspase-8-dimer ") (species [GK_48887])) ([GK_2671812] of Complex (_displayName "[Hsa] TRAF2:TRADD:RIP1:FADD:procaspase-8-dimer [cytosol]") (compartment [GK_70101]) (DB_ID 2671812) (hasComponent [GK_140977] [GK_2671817]) (isChimeric FALSE) (name "TRAF2:TRADD:RIP1:FADD:procaspase-8-dimer") (species [GK_48887])) ([GK_2671813] of DefinedSet (_displayName "[Hsa] DISC:procaspase-8-dimer [plasma membrane]") (compartment [GK_876] [GK_70101]) (DB_ID 2671813) (hasMember [GK_2671811] [GK_2671812] [GK_2671816]) (name "DISC:procaspase-8-dimer" "death-inducing signaling complex:procaspase-8-dimer") (species [GK_48887])) ([GK_2671814] of DefinedSet (_displayName "[Hsa] DISC [plasma membrane]") (compartment [GK_876] [GK_70101]) (DB_ID 2671814) (hasMember [GK_43124] [GK_140977] [GK_141137]) (name "DISC" "death-inducing signaling complex") (species [GK_48887])) ([GK_2671816] of Complex (_displayName "[Hsa] TRAIL:TRAIL receptor-2:FADD:procaspase-8-dimer [plasma membrane]") (compartment [GK_876]) (DB_ID 2671816) (hasComponent [GK_141137] [GK_2671817]) (isChimeric FALSE) (name "TRAIL:TRAIL receptor-2:FADD:procaspase-8-dimer") (species [GK_48887])) ([GK_2671817] of Complex (_displayName "[Hsa] procaspase-8 dimer [cytosol]") (compartment [GK_70101]) (DB_ID 2671817) (hasComponent [GK_57031] [GK_57031]) (isChimeric FALSE) (name "procaspase-8 dimer") (species [GK_48887])) ([GK_2671823] of Person (_displayName "Zerbe, O") (DB_ID 2671823) (firstname "O") (initial "O") (surname "Zerbe")) ([GK_2671824] of Person (_displayName "Keller, N") (DB_ID 2671824) (firstname "N") (initial "N") (surname "Keller")) ([GK_2671825] of LiteratureReference (_displayName "Studies of the molecular mechanism of caspase-8 activation by solution NMR") (author [GK_2671824] [GK_2562587] [GK_2671823]) (DB_ID 2671825) (journal "Cell Death Differ.") (pages "710-8") (pubMedIdentifier 19851329) (title "Studies of the molecular mechanism of caspase-8 activation by solution NMR") (volume 17) (year 2010)) ([GK_2671826] of InstanceEdit (_displayName "Shamovsky, V, 2012-11-26") (author [GK_429259]) (dateTime "2012-11-26 04:21:07") (DB_ID 2671826)) ([GK_2672161] of Person (_displayName "Jassoy, C") (DB_ID 2672161) (firstname "C") (initial "C") (surname "Jassoy")) ([GK_2672165] of LiteratureReference (_displayName "Target protease specificity of the viral serpin CrmA. Analysis of five caspases") (author [GK_2672211] [GK_2672179] [GK_2672202] [GK_2672176] [GK_2672188] [GK_2534135]) (DB_ID 2672165) (journal "J. Biol. Chem.") (pages "7797-800") (pubMedIdentifier 9065443) (title "Target protease specificity of the viral serpin CrmA. Analysis of five caspases") (volume 272) (year 1997)) ([GK_2672168] of Person (_displayName "Miura, M") (DB_ID 2672168) (firstname "M") (initial "M") (surname "Miura")) ([GK_2672171] of Person (_displayName "Smith, G L") (DB_ID 2672171) (firstname "G L") (initial "GL") (surname "Smith")) ([GK_2672173] of LiteratureReference (_displayName "Tumor necrosis factor-induced apoptosis is mediated by a CrmA-sensitive cell death pathway") (author [GK_2672168] [GK_2672206] [GK_2672200]) (DB_ID 2672173) (journal "Proc. Natl. Acad. Sci. U.S.A.") (pages "8318-22") (pubMedIdentifier 7667287) (title "Tumor necrosis factor-induced apoptosis is mediated by a CrmA-sensitive cell death pathway") (volume 92) (year 1995)) ([GK_2672176] of Person (_displayName "Muzio, M") (DB_ID 2672176) (firstname "M") (initial "M") (surname "Muzio")) ([GK_2672179] of Person (_displayName "Snipas, S") (DB_ID 2672179) (firstname "S") (initial "S") (surname "Snipas")) ([GK_2672185] of LiteratureReference (_displayName "Fas- and tumor necrosis factor-induced apoptosis is inhibited by the poxvirus crmA gene product") (author [GK_2672222] [GK_2672188]) (DB_ID 2672185) (journal "J. Biol. Chem.") (pages "3255-60") (pubMedIdentifier 7531702) (title "Fas- and tumor necrosis factor-induced apoptosis is inhibited by the poxvirus crmA gene product") (volume 270) (year 1995)) ([GK_2672186] of Person (_displayName "Ehret, R") (DB_ID 2672186) (firstname "R") (initial "R") (surname "Ehret")) ([GK_2672188] of Person (_displayName "Dixit, V M") (DB_ID 2672188) (firstname "V M") (initial "VM") (surname "Dixit")) ([GK_2672191] of Summation (_displayName "SPI-2/CrmA (cytokine response modifier A) is a poxvirus gen...") (DB_ID 2672191) (text "SPI-2/CrmA (cytokine response modifier A) is a poxvirus gene product with homology to members of the serpin (serine protease inhibitor) superfamily. Cowpox virus-derived and vaccinia virus-derived CrmA cDNAs transfected into cells can inhibit apoptosis induced by Fas-ligation and activation of the tumor necrosis factor receptor [Tewari M and Dixit VM 1995; Miura M et al 1995; Kettle S et al 1997]. Cowpox virus-derived CrmA was shown to selectively inhibit caspases in Fas-mediated apoptosis, showing the highest affinity for interleukin-1 beta-converting enzyme (ICE) and the second highest for the caspase-8 with Ki = 0.95 nM [Zhou Q et al 1997].")) ([GK_2672196] of Reaction (_displayName "[Hsa] Viral SPI-2 blocks caspase-8 activity") (_doRelease FALSE) (compartment [GK_70101]) (DB_ID 2672196) (input [GK_2562550] [GK_2672224]) (isChimeric FALSE) (literatureReference [GK_2672185] [GK_2672213] [GK_2672173] [GK_2672165]) (name "Viral SPI-2 blocks caspase-8 activity") (output [GK_2672221]) (precedingEvent [GK_139952]) (species [GK_48887]) (summation [GK_2672191])) ([GK_2672198] of Person (_displayName "Alcamí, A") (DB_ID 2672198) (firstname "A") (initial "A") (surname "Alcamí")) ([GK_2672199] of Person (_displayName "Khanna, A") (DB_ID 2672199) (firstname "A") (initial "A") (surname "Khanna")) ([GK_2672200] of Person (_displayName "Yuan, J") (DB_ID 2672200) (firstname "J") (initial "J") (surname "Yuan")) ([GK_2672202] of Person (_displayName "Orth, K") (DB_ID 2672202) (firstname "K") (initial "K") (surname "Orth")) ([GK_2672206] of Person (_displayName "Friedlander, R M") (DB_ID 2672206) (firstname "R M") (initial "RM") (surname "Friedlander")) ([GK_2672208] of Person (_displayName "Kettle, S") (DB_ID 2672208) (firstname "S") (initial "S") (surname "Kettle")) ([GK_2672211] of Person (_displayName "Zhou, Q") (DB_ID 2672211) (firstname "Q") (initial "Q") (surname "Zhou")) ([GK_2672213] of LiteratureReference (_displayName "Vaccinia virus serpin B13R (SPI-2) inhibits interleukin-1beta-converting enzyme and protects virus-infected cells from TNF- and Fas-mediated apoptosis, but does not prevent IL-1beta-induced fever") (author [GK_2672208] [GK_2672198] [GK_2672199] [GK_2672186] [GK_2672161] [GK_2672171]) (DB_ID 2672213) (journal "J. Gen. Virol.") (pages "677-85") (pubMedIdentifier 9049422) (title "Vaccinia virus serpin B13R (SPI-2) inhibits interleukin-1beta-converting enzyme and protects virus-infected cells from TNF- and Fas-mediated apoptosis, but does not prevent IL-1beta-induced fever") (volume 78) (year 1997)) ([GK_2672221] of Complex (_displayName "[Hsa] acctive caspase-8:viral SPI-2 [cytosol]") (compartment [GK_70101]) (DB_ID 2672221) (hasComponent [GK_2562550] [GK_2672224]) (isChimeric FALSE) (name "acctive caspase-8:viral SPI-2") (species [GK_48887] [GK_2671792] [GK_2671785])) ([GK_2672222] of Person (_displayName "Tewari, M") (DB_ID 2672222) (firstname "M") (initial "M") (surname "Tewari")) ([GK_2672224] of DefinedSet (_displayName "[Cvi] viral SPI-2 [cytosol]") (compartment [GK_70101]) (DB_ID 2672224) (hasMember [GK_2671784] [GK_2671786]) (name "viral SPI-2" "viral serpins") (species [GK_2671792] [GK_2671785])) ([GK_2741] of GO_MolecularFunction (_displayName "cysteine-type peptidase activity") (accession "0008234") (DB_ID 2741) (definition "Catalysis of the hydrolysis of peptide bonds in a polypeptide chain by a mechanism in which the sulfhydryl group of a cysteine residue at the active center acts as a nucleophile.") (instanceOf [GK_376448]) (name "cysteine-type peptidase activity") (referenceDatabase [GK_1])) ([GK_29497] of DatabaseIdentifier (_displayName "COMPOUND:C00076") (DB_ID 29497) (identifier "C00076") (referenceDatabase [GK_6])) ([GK_2984174] of LiteratureReference (_displayName "TNF-alpha induces two distinct caspase-8 activation pathways") (author [GK_2984177] [GK_2984180] [GK_2584552]) (DB_ID 2984174) (journal "Cell") (pages "693-703") (pubMedIdentifier 18485876) (title "TNF-alpha induces two distinct caspase-8 activation pathways") (volume 133) (year 2008)) ([GK_2984175] of Person (_displayName "Hughes, Michelle A") (DB_ID 2984175) (firstname "Michelle A") (initial "MA") (surname "Hughes")) ([GK_2984176] of Person (_displayName "Butterworth, Michael") (DB_ID 2984176) (firstname "Michael") (initial "M") (surname "Butterworth")) ([GK_2984177] of Person (_displayName "Wang, Lai") (DB_ID 2984177) (firstname "Lai") (initial "L") (surname "Wang")) ([GK_2984178] of Person (_displayName "Cohen, Gerald M") (DB_ID 2984178) (firstname "Gerald M") (initial "GM") (surname "Cohen")) ([GK_2984180] of Person (_displayName "Du, Fenghe") (DB_ID 2984180) (firstname "Fenghe") (initial "F") (surname "Du")) ([GK_2984182] of Person (_displayName "Harper, Nicholas") (DB_ID 2984182) (firstname "Nicholas") (initial "N") (surname "Harper")) ([GK_2984185] of LiteratureReference (_displayName "Reconstitution of the death-inducing signaling complex reveals a substrate switch that determines CD95-mediated death or survival") (author [GK_2984175] [GK_2984182] [GK_2984176] [GK_2562560] [GK_2984178] [GK_2562548]) (DB_ID 2984185) (journal "Mol. Cell") (pages "265-79") (pubMedIdentifier 19683492) (title "Reconstitution of the death-inducing signaling complex reveals a substrate switch that determines CD95-mediated death or survival") (volume 35) (year 2009)) ([GK_30151] of DatabaseIdentifier (_displayName "COMPOUND:C00434") (DB_ID 30151) (identifier "C00434") (referenceDatabase [GK_6])) ([GK_3132308] of GO_BiologicalProcess (_displayName "single-organism cellular process") (accession "0044763") (DB_ID 3132308) (definition "Any process that is carried out at the cellular level, occurring within a single organism.") (instanceOf [GK_143] [GK_2587987]) (name "single-organism cellular process") (referenceDatabase [GK_1])) ([GK_3320] of GO_BiologicalProcess (_displayName "regulation of metabolic process") (accession "0019222") (DB_ID 3320) (definition "Any process that modulates the frequency, rate or extent of the chemical reactions and pathways within a cell or an organism.") 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(instanceOf [GK_258147]) (name "intracellular") (referenceDatabase [GK_1])) ([GK_355446] of ReferenceGeneProduct (_displayName "[Hsa] UniProt:P68431 HIST1H3A recommendedName: Histone H3.1 alternativeName: Histone H3/a alternativeName: Histone H3/b alternativeName: Histone H3/c alternativeName: Histone H3/d alternativeName: Histone H3/f alternativeName: Histone H3/h alternativeName: Histone H3/i alternativeName: Histone H3/j alternativeName: Histone H3/k alternativeName: Histone H3/l ") (checksum "1") (comment "FUNCTION Core component of nucleosome. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling.SUBUNIT The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA.DEVELOPMENTAL STAGE Expressed during S phase, then expression strongly decreases as cell division slows down during the process of differentiation.PTM Acetylation is generally linked to gene activation. Acetylation on Lys-10 (H3K9ac) impairs methylation at Arg-9 (H3R8me2s). Acetylation on Lys-19 (H3K18ac) and Lys-24 (H3K24ac) favors methylation at Arg-18 (H3R17me).PTM Citrullination at Arg-9 (H3R8ci) and/or Arg-18 (H3R17ci) by PADI4 impairs methylation and represses transcription.PTM Asymmetric dimethylation at Arg-18 (H3R17me2a) by CARM1 is linked to gene activation. Symmetric dimethylation at Arg-9 (H3R8me2s) by PRMT5 is linked to gene repression. Asymmetric dimethylation at Arg-3 (H3R2me2a) by PRMT6 is linked to gene repression and is mutually exclusive with H3 Lys-5 methylation (H3K4me2 and H3K4me3). H3R2me2a is present at the 3' of genes regardless of their transcription state and is enriched on inactive promoters, while it is absent on active promoters.PTM Methylation at Lys-5 (H3K4me), Lys-37 (H3K36me) and Lys-80 (H3K79me) are linked to gene activation. Methylation at Lys-5 (H3K4me) facilitates subsequent acetylation of H3 and H4. Methylation at Lys-80 (H3K79me) is associated with DNA double-strand break (DSB) responses and is a specific target for TP53BP1. Methylation at Lys-10 (H3K9me) and Lys-28 (H3K27me) are linked to gene repression. Methylation at Lys-10 (H3K9me) is a specific target for HP1 proteins (CBX1, CBX3 and CBX5) and prevents subsequent phosphorylation at Ser-11 (H3S10ph) and acetylation of H3 and H4. Methylation at Lys-5 (H3K4me) and Lys-80 (H3K79me) require preliminary monoubiquitination of H2B at 'Lys-120'. Methylation at Lys-10 (H3K9me) and Lys-28 (H3K27me) are enriched in inactive X chromosome chromatin.MISCELLANEOUS This histone is only present in mammals and is enriched in acetylation of Lys-15 and dimethylation of Lys-10 (H3K9me2).SIMILARITY Belongs to the histone H3 family.") 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Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling.SUBUNIT The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA. During nucleosome assembly the chaperone ASF1A interacts with the histone H3-H4 heterodimer.DEVELOPMENTAL STAGE Expressed during S phase, then expression strongly decreases as cell division slows down during the process of differentiation.PTM Acetylation is generally linked to gene activation. Acetylation on Lys-10 (H3K9ac) impairs methylation at Arg-9 (H3R8me2s). Acetylation on Lys-19 (H3K18ac) and Lys-24 (H3K24ac) favors methylation at Arg-18 (H3R17me).PTM Citrullination at Arg-9 (H3R8ci) and/or Arg-18 (H3R17ci) by PADI4 impairs methylation and represses transcription.PTM Asymmetric dimethylation at Arg-18 (H3R17me2a) by CARM1 is linked to gene activation. Symmetric dimethylation at Arg-9 (H3R8me2s) by PRMT5 is linked to gene repression. Asymmetric dimethylation at Arg-3 (H3R2me2a) by PRMT6 is linked to gene repression and is mutually exclusive with H3 Lys-5 methylation (H3K4me2 and H3K4me3). H3R2me2a is present at the 3' of genes regardless of their transcription state and is enriched on inactive promoters, while it is absent on active promoters.PTM Methylation at Lys-5 (H3K4me), Lys-37 (H3K36me) and Lys-80 (H3K79me) are linked to gene activation. Methylation at Lys-5 (H3K4me) facilitates subsequent acetylation of H3 and H4. Methylation at Lys-80 (H3K79me) is associated with DNA double-strand break (DSB) responses and is a specific target for TP53BP1. Methylation at Lys-10 (H3K9me) and Lys-28 (H3K27me) are linked to gene repression. Methylation at Lys-10 (H3K9me) is a specific target for HP1 proteins (CBX1, CBX3 and CBX5) and prevents subsequent phosphorylation at Ser-11 (H3S10ph) and acetylation of H3 and H4. Methylation at Lys-5 (H3K4me) and Lys-80 (H3K79me) require preliminary monoubiquitination of H2B at 'Lys-120'. Methylation at Lys-10 (H3K9me) and Lys-28 (H3K27me) are enriched in inactive X chromosome chromatin.SIMILARITY Belongs to the histone H3 family.") (DB_ID 355447) (description "recommendedName: Histone H3.2 alternativeName: Histone H3/m alternativeName: Histone H3/o ") (geneName "HIST2H3A" "" "" "HIST2H3C" "H3F2" "H3FM" "" "" "HIST2H3D") (identifier "Q71DI3") (isSequenceChanged TRUE) (keyword "3D-structure" "Acetylation" "Chromosome" "Citrullination" "Complete proteome" "Direct protein sequencing" "DNA-binding" "Methylation" "Nucleosome core" "Nucleus" "Phosphoprotein" "Polymorphism" "Ubl conjugation") (name "HIST2H3A") (referenceDatabase [GK_2]) (secondaryIdentifier "H32_HUMAN" "A2BDF6" "A6NFS4" "Q6B053") (sequenceLength 136) (species [GK_48887])) ([GK_355448] of ReferenceGeneProduct (_displayName "[Hsa] UniProt:P84243 H3F3A recommendedName: Histone H3.3 ") (checksum "1") (comment "DEVELOPMENTAL STAGE Expressed throughout the cell cycle independently of DNA synthesis.PTM Acetylation is generally linked to gene activation. Acetylation on Lys-10 (H3K9ac) impairs methylation at Arg-9 (H3R8me2s). Acetylation on Lys-19 (H3K18ac) and Lys-24 (H3K24ac) favors methylation at Arg-18 (H3R17me).PTM Citrullination at Arg-9 (H3R8ci) and/or Arg-18 (H3R17ci) by PADI4 impairs methylation and represses transcription.PTM Asymmetric dimethylation at Arg-18 (H3R17me2a) by CARM1 is linked to gene activation. Symmetric dimethylation at Arg-9 (H3R8me2s) by PRMT5 is linked to gene repression. Asymmetric dimethylation at Arg-3 (H3R2me2a) by PRMT6 is linked to gene repression and is mutually exclusive with H3 Lys-5 methylation (H3K4me2 and H3K4me3). H3R2me2a is present at the 3' of genes regardless of their transcription state and is enriched on inactive promoters, while it is absent on active promoters.PTM Specifically enriched in modifications associated with active chromatin such as methylation at Lys-5 (H3K4me), Lys-37 and Lys-80. Methylation at Lys-5 (H3K4me) facilitates subsequent acetylation of H3 and H4. Methylation at Lys-80 (H3K79me) is associated with DNA double-strand break (DSB) responses and is a specific target for TP53BP1. Methylation at Lys-10 (H3K9me) and Lys-28 (H3K27me), which are linked to gene repression, are underrepresented. Methylation at Lys-10 (H3K9me) is a specific target for HP1 proteins (CBX1, CBX3 and CBX5) and prevents subsequent phosphorylation at Ser-11 (H3S10ph) and acetylation of H3 and H4. Methylation at Lys-5 (H3K4me) and Lys-80 (H3K79me) require preliminary monoubiquitination of H2B at 'Lys-120'. Methylation at Lys-10 (H3K9me) and Lys-28 (H3K27me) are enriched in inactive X chromosome chromatin.SIMILARITY Belongs to the histone H3 family.") (DB_ID 355448) (description "recommendedName: Histone H3.3 ") (geneName "H3F3A" "H3.3A" "H3F3" "PP781" "" "" "H3F3B" "H3.3B") (identifier "P84243") (isSequenceChanged TRUE) (keyword "3D-structure" "Acetylation" "Chromosome" "Citrullination" "Complete proteome" "Direct protein sequencing" "DNA-binding" "Methylation" "Nucleosome core" "Nucleus" "Phosphoprotein" "Ubl conjugation") (name "H3F3A") (referenceDatabase [GK_2]) (secondaryIdentifier "H33_HUMAN" "P06351" "P33155" "Q5VV55" "Q5VV56" "Q66I33" "Q9V3W4") (sequenceLength 136) (species [GK_48887])) ([GK_355449] of ReferenceGeneProduct (_displayName "[Hsa] UniProt:P62805 HIST1H4A recommendedName: Histone H4 ") (checksum "1") (comment "FUNCTION Core component of nucleosome. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling.SUBUNIT The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA.PTM Acetylation at Lys-6 (H4K5ac), Lys-9 (H4K8ac), Lys-13 (H4K12ac) and Lys-17 (H4K16ac) occurs in coding regions of the genome but not in heterochromatin.PTM Citrullination at Arg-4 (H4R3ci) by PADI4 impairs methylation.PTM Monomethylation and asymmetric dimethylation at Arg-4 (H4R3me1 and H4R3me2a, respectively) by PRMT1 favors acetylation at Lys-9 (H4K8ac) and Lys-13 (H4K12ac). Demethylation is performed by JMJD6. Symmetric dimethylation on Arg-4 (H4R3me2s) by the PRDM1/PRMT5 complex may play a crucial role in the germ-cell lineage.SIMILARITY Belongs to the histone H4 family.") 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Includes the plasma membrane and any external encapsulating structures such as the cell wall and cell envelope.") (instanceOf [GK_357]) (name "cell") (referenceDatabase [GK_1])) ([GK_357] of GO_CellularComponent (_displayName "cellular_component") (accession "0005575") (DB_ID 357) (definition "The part of a cell or its extracellular environment in which a gene product is located. A gene product may be located in one or more parts of a cell and its location may be as specific as a particular macromolecular complex, that is, a stable, persistent association of macromolecules that function together.") 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(instanceOf [GK_160483]) (name "other organism") (referenceDatabase [GK_1])) ([GK_447577] of GO_CellularComponent (_displayName "other organism part") (accession "0044217") (componentOf [GK_447576]) (DB_ID 447577) (definition "Any constituent part of a secondary organism with which the first organism is interacting.") (instanceOf [GK_258201]) (name "other organism part") (referenceDatabase [GK_1])) ([GK_448179] of PsiMod (_displayName "N6-myristoyl-L-lysine [MOD:00087]") (DB_ID 448179) (definition "A protein modification that effectively converts an L-lysine residue to N6-myristoyl-L-lysine.") (identifier "00087") (name "N6-myristoyl-L-lysine") (referenceDatabase [GK_437354]) (synonym "(S)-2-amino-6-(tetradecanoylamino)hexanoic acid" "N6-myristoyl lysine" "N6MyrLys" "N6-myristoylated L-lysine" "Myristoylation" "Myristoyl")) ([GK_448182] of PsiMod (_displayName "half cystine [MOD:00798]") (DB_ID 448182) (definition "A protein modification that can be regarded as effectively either one half of a cystine cross-link, or a cysteine residue with one hydrogen atom or proton removed.") (identifier "00798") (name "half cystine") (referenceDatabase [GK_437354]) (synonym "Half of a disulfide bridge" "Dehydro")) ([GK_450] of GO_MolecularFunction (_displayName "hydrolase activity") (accession "0016787") (DB_ID 450) (definition "Catalysis of the hydrolysis of various bonds, e.g. C-O, C-N, C-C, phosphoric anhydride bonds, etc. Hydrolase is the systematic name for any enzyme of EC class 3.") (ecNumber "3" "3" "3" "3" "3" "3" "3" "3" "3" "3" "3" "3" "3" "3" "3" "3" "3") (instanceOf [GK_97]) (name "hydrolase activity") (referenceDatabase [GK_1])) ([GK_452043] of Person (_displayName "Shin, H") (DB_ID 452043) (firstname "Hyunshun") (initial "H") (surname "Shin")) ([GK_452587] of Person (_displayName "Betsholtz, C") (DB_ID 452587) (initial "C") (surname "Betsholtz")) ([GK_459] of Compartment (_displayName "cytoplasm") (accession "0005737") (DB_ID 459) (definition "All of the contents of a cell excluding the plasma membrane and nucleus, but including other subcellular structures.") (instanceOf [GK_258148]) (name "cytoplasm") (referenceDatabase [GK_1])) ([GK_469669] of Person (_displayName "Gilbey, SG") (DB_ID 469669) (initial "SG") (surname "Gilbey")) ([GK_480491] of Person (_displayName "Heinzmann, C") (DB_ID 480491) (initial "C") (surname "Heinzmann")) ([GK_48887] of Species (_displayName "Homo sapiens") (crossReference [GK_72938]) (DB_ID 48887) (name "Homo sapiens" "H. sapiens" "Hs" "human" "man") (superTaxon [GK_72939])) ([GK_49984] of ReferenceGeneProduct (_displayName "[Hsa] UniProt:P01160 NPPA recommendedName: Natriuretic peptides A alternativeName: CDD-ANF alternativeName: Prepronatriodilatin component recommendedName: Cardiodilatin-related peptide shortName:CDP /component component recommendedName: Atrial natriuretic factor shortName:ANF alternativeName: Atrial natriuretic peptide shortName:ANP /component") (checksum "1") (comment "PTM Cleaved by CORIN upon secretion to produce the functional hormone.POLYMORPHISM There are two different prepronatriodilatin alleles. One codes for 2 Arg residues at the C-terminus that are cleaved to form the mature peptide, while the other ends in a termination codon immediately after the last codon of the mature peptide.SIMILARITY Belongs to the natriuretic peptide family.") (DB_ID 49984) (description "recommendedName: Natriuretic peptides A alternativeName: CDD-ANF alternativeName: Prepronatriodilatin component recommendedName: Cardiodilatin-related peptide shortName:CDP /component component recommendedName: Atrial natriuretic factor shortName:ANF alternativeName: Atrial natriuretic peptide shortName:ANP /component") (geneName "NPPA" "ANP" "PND") (identifier "P01160") (isSequenceChanged TRUE) (keyword "3D-structure" "Atrial fibrillation" "Complete proteome" "Direct protein sequencing" "Disulfide bond" "Hormone" "Polymorphism" "Secreted" "Signal" "Vasoactive") (name "NPPA") (referenceDatabase [GK_2]) (secondaryIdentifier "ANF_HUMAN" "Q13766" "Q5JZE1") (sequenceLength 153) (species [GK_48887])) ([GK_500144] of Person (_displayName "Baker, D") (DB_ID 500144) (firstname "David") (initial "D") (surname "Baker")) ([GK_500361] of Person (_displayName "Peng, S") (DB_ID 500361) (initial "S") (surname "Peng")) ([GK_50094] of ReferenceGeneProduct (_displayName "[Hsa] UniProt:P02647 APOA1 recommendedName: Apolipoprotein A-I shortName:Apo-AI shortName:ApoA-I alternativeName: Apolipoprotein A1 component recommendedName: Apolipoprotein A-I(1-242) /component") (checksum "1") (comment "PTM Phosphorylation sites are present in the extracelllular medium.SIMILARITY Belongs to the apolipoprotein A1/A4/E family.") (DB_ID 50094) (description "recommendedName: Apolipoprotein A-I shortName:Apo-AI shortName:ApoA-I alternativeName: Apolipoprotein A1 component recommendedName: Apolipoprotein A-I(1-242) /component") (geneName "APOA1") (identifier "P02647") (isSequenceChanged TRUE) (keyword "3D-structure" "Amyloid" "Amyloidosis" "Atherosclerosis" "Cholesterol metabolism" "Complete proteome" "Direct protein sequencing" "Disease mutation" "Glycation" "Glycoprotein" "HDL" "Lipid metabolism" "Lipid transport" "Lipoprotein" "Neuropathy" "Palmitate" "Phosphoprotein" "Polymorphism" "Repeat" "Secreted" "Signal" "Steroid metabolism" "Transport") (name "APOA1") (referenceDatabase [GK_2]) (secondaryIdentifier "APOA1_HUMAN" "A8K866" "Q6LDN9" "Q6Q785" "Q9UCS8" "Q9UCT8") (sequenceLength 267) (species [GK_48887])) ([GK_50098] of ReferenceGeneProduct (_displayName "[Hsa] UniProt:P06727 APOA4 recommendedName: Apolipoprotein A-IV shortName:Apo-AIV shortName:ApoA-IV alternativeName: Apolipoprotein A4 ") (checksum "1") (comment "FUNCTION May have a role in chylomicrons and VLDL secretion and catabolism. Required for efficient activation of lipoprotein lipase by ApoC-II; potent activator of LCAT. Apoa-IV is a major component of HDL and chylomicrons.DOMAIN Nine of the thirteen 22-amino acid tandem repeats (each 22-mer is actually a tandem array of two, A and B, related 11-mers) occurring in this sequence are predicted to be highly alpha-helical, and many of these helices are amphipathic. They may therefore serve as lipid-binding domains with lecithin:cholesterol acyltransferase (LCAT) activating abilities.PTM Phosphorylation sites are present in the extracelllular medium.POLYMORPHISM Eight alleles have been characterized (APOA-IV*0 to APOA-IV*7). APOA-IV*1 is the major allele (90%), APOA-IV*2 is also common (8%), the others are rare alleles. The sequence shown represents allele APOA-IV*1.SIMILARITY Belongs to the apolipoprotein A1/A4/E family.") (DB_ID 50098) (description "recommendedName: Apolipoprotein A-IV shortName:Apo-AIV shortName:ApoA-IV alternativeName: Apolipoprotein A4 ") (geneName "APOA4") (identifier "P06727") (isSequenceChanged TRUE) (keyword "Chylomicron" "Complete proteome" "HDL" "Lipid transport" "Phosphoprotein" "Polymorphism" "Repeat" "Secreted" "Signal" "Transport") (name "APOA4") (referenceDatabase [GK_2]) (secondaryIdentifier "APOA4_HUMAN" "A8MSL6" "Q14CW8" "Q6Q787") (sequenceLength 396) (species [GK_48887])) ([GK_504] of GO_BiologicalProcess (_displayName "metabolic process") (accession "0008152") (DB_ID 504) (definition "The chemical reactions and pathways, including anabolism and catabolism, by which living organisms transform chemical substances. Metabolic processes typically transform small molecules, but also include macromolecular processes such as DNA repair and replication, and protein synthesis and degradation.") (instanceOf [GK_106]) (name "metabolic process") (referenceDatabase [GK_1])) ([GK_50591] of ReferenceGeneProduct (_displayName "[Hsa] UniProt:P61769 B2M recommendedName: Beta-2-microglobulin component recommendedName: Beta-2-microglobulin form pI 5.3 /component") (checksum "1") (comment "FUNCTION Component of the class I major histocompatibility complex (MHC). Involved in the presentation of peptide antigens to the immune system.PTM Glycation of Ile-21 is observed in long-term hemodialysis patients.SIMILARITY Belongs to the beta-2-microglobulin family.SIMILARITY Contains 1 Ig-like C1-type (immunoglobulin-like) domain.") (DB_ID 50591) (description "recommendedName: Beta-2-microglobulin component recommendedName: Beta-2-microglobulin form pI 5.3 /component") (geneName "B2M" "CDABP0092" "HDCMA22P") (identifier "P61769") (isSequenceChanged TRUE) (keyword "3D-structure" "Amyloid" "Amyloidosis" "Complete proteome" "Direct protein sequencing" "Disease mutation" "Disulfide bond" "Glycation" "Glycoprotein" "Immunity" "Immunoglobulin domain" "MHC I" "Pyrrolidone carboxylic acid" "Secreted" "Signal") (name "B2M") (referenceDatabase [GK_2]) (secondaryIdentifier "B2MG_HUMAN" "P01884" "Q540F8" "Q6IAT8" "Q9UCK0" "Q9UD48" "Q9UDF4") (sequenceLength 119) (species [GK_48887])) ([GK_50810] of ReferenceGeneProduct (_displayName "[Hsa] UniProt:Q15582 TGFBI recommendedName: Transforming growth factor-beta-induced protein ig-h3 shortName:Beta ig-h3 alternativeName: Kerato-epithelin alternativeName: RGD-containing collagen-associated protein shortName:RGD-CAP alternativeName: RGD-containing collagen-associated protein shortName:RGD-CAP ") (checksum "1") (comment "FUNCTION Binds to type I, II, and IV collagens. This adhesion protein may play an important role in cell-collagen interactions. In cartilage, may be involved in endochondral bone formation.INDUCTION By TGFB1.DISEASE Defects in TGFBI are the cause of corneal dystrophy lattice type 1 (CDL1) [MIM:122200]. Inheritance is autosomal dominant.DISEASE Defects in TGFBI are a cause of corneal dystrophy Thiel-Behnke type (CDTB) [MIM:602082]; also known as corneal dystrophy of Bowman layer type 2 (CDB2).DISEASE Defects in TGFBI are the cause of Avellino corneal dystrophy (ACD) [MIM:607541]. ACD could be considered a variant of granular dystrophy with a significant amyloidogenic tendency. Inheritance is autosomal dominant.SIMILARITY Contains 1 EMI domain.SIMILARITY Contains 4 FAS1 domains.") (DB_ID 50810) (description "recommendedName: Transforming growth factor-beta-induced protein ig-h3 shortName:Beta ig-h3 alternativeName: Kerato-epithelin alternativeName: RGD-containing collagen-associated protein shortName:RGD-CAP alternativeName: RGD-containing collagen-associated protein shortName:RGD-CAP ") (geneName "TGFBI" "BIGH3") (identifier "Q15582") (isSequenceChanged TRUE) (keyword "3D-structure" "Amyloid" "Cell adhesion" "Complete proteome" "Disease mutation" "Disulfide bond" "Extracellular matrix" "Gamma-carboxyglutamic acid" "Polymorphism" "Repeat" "Secreted" "Sensory transduction" "Signal" "Vision") (name "TGFBI") (referenceDatabase [GK_2]) (secondaryIdentifier "BGH3_HUMAN" "D3DQB1" "O14471" "O14472" "O14476" "O43216" "O43217" "O43218" "O43219" "Q53XM1") (sequenceLength 683) (species [GK_48887])) ([GK_517749] of Person (_displayName "Hudson, J") (DB_ID 517749) (initial "J") (surname "Hudson")) ([GK_53331] of ReferenceGeneProduct (_displayName "[Hsa] UniProt:P01034 CST3 recommendedName: Cystatin-C alternativeName: Cystatin-3 alternativeName: Gamma-trace alternativeName: Neuroendocrine basic polypeptide alternativeName: Post-gamma-globulin ") (checksum "1") (comment "FUNCTION As an inhibitor of cysteine proteinases, this protein is thought to serve an important physiological role as a local regulator of this enzyme activity.SUBUNIT Homodimer.MISCELLANEOUS Potential cerebrospinal fluid marker for the diagnosis of Creutzfeldt-Jakob disease.SIMILARITY Belongs to the cystatin family.") (DB_ID 53331) (description "recommendedName: Cystatin-C alternativeName: Cystatin-3 alternativeName: Gamma-trace alternativeName: Neuroendocrine basic polypeptide alternativeName: Post-gamma-globulin ") (geneName "CST3") (identifier "P01034") (isSequenceChanged TRUE) (keyword "3D-structure" "Age-related macular degeneration" "Amyloid" "Amyloidosis" "Complete proteome" "Direct protein sequencing" "Disease mutation" "Disulfide bond" "Glycoprotein" "Polymorphism" "Protease inhibitor" "Secreted" "Signal" "Thiol protease inhibitor") (name "CST3") (referenceDatabase [GK_2]) (secondaryIdentifier "CYTC_HUMAN" "B2R5J9" "D3DW42" "Q6FGW9") (sequenceLength 146) (species [GK_48887])) ([GK_538696] of Person (_displayName "Enghild, JJ") (DB_ID 538696) (initial "JJ") (surname "Enghild")) ([GK_54639] of EntityWithAccessionedSequence (_displayName "[Hsa] FADD [cytosol]") (compartment [GK_70101]) (DB_ID 54639) (endCoordinate 208) (literatureReference [GK_140483]) (name "FADD" "FADD protein (FAS-associating death domain-containing protein) (Mediator of receptor induced toxicity)" "FADD protein" "FAS-associating death domain-containing protein" "Mediator of receptor induced toxicity") (referenceEntity [GK_54640]) (species [GK_48887]) (stableIdentifier [GK_365546]) (startCoordinate 1)) ([GK_54640] of ReferenceGeneProduct (_displayName "[Hsa] UniProt:Q13158 FADD recommendedName: Protein FADD alternativeName: FAS-associated death domain protein alternativeName: FAS-associating death domain-containing protein alternativeName: Growth-inhibiting gene 3 protein alternativeName: Mediator of receptor induced toxicity ") (checksum "0E65E2F852E83507") (comment "FUNCTION Apoptotic adaptor molecule that recruits caspase-8 or caspase-10 to the activated Fas (CD95) or TNFR-1 receptors. The resulting aggregate called the death-inducing signaling complex (DISC) performs caspase-8 proteolytic activation. Active caspase-8 initiates the subsequent cascade of caspases mediating apoptosis. Involved in interferon-mediated antiviral immune response, playing a role in the positive regulation of interferon signaling.SUBUNIT Can self-associate. Interacts with CFLAR, PEA15 and MBD4. When phosphorylated, part of a complex containing HIPK3 and FAS. May interact with MAVS/IPS1. Interacts with MOCV v-CFLAR protein and LRDD. Interacts (via death domain) with FAS (via death domain). Interacts with CASP8.TISSUE SPECIFICITY Expressed in a wide variety of tissues, except for peripheral blood mononuclear leukocytes.DOMAIN Contains a death domain involved in the binding of the corresponding domain within Fas receptor.DOMAIN The interaction between the FAS and FADD death domains is crucial for the formation of the death-inducing signaling complex (DISC).DISEASE Defects in FADD are the cause of infections recurrent associated with encephalopathy hepatic dysfunction and cardiovascular malformations (IEHDCM) [MIM:613759]. A condition with biological features of autoimmune lymphoproliferative syndrome such as high-circulating CD4(-)CD8(-)TCR-alpha-beta(+) T-cell counts, and elevated IL10 and FASL levels. Affected individuals suffer from recurrent, stereotypical episodes of fever, encephalopathy, and mild liver dysfunction sometimes accompanied by generalized seizures. The episodes can be triggered by varicella zoster virus (VZV), measles mumps rubella (MMR) attenuated vaccine, parainfluenza virus, and Epstein-Barr virus (EBV).SIMILARITY Contains 1 death domain.SIMILARITY Contains 1 DED (death effector) domain.") (DB_ID 54640) (description "recommendedName: Protein FADD alternativeName: FAS-associated death domain protein alternativeName: FAS-associating death domain-containing protein alternativeName: Growth-inhibiting gene 3 protein alternativeName: Mediator of receptor induced toxicity ") (geneName "FADD" "MORT1" "GIG3") (identifier "Q13158") (isSequenceChanged TRUE) (keyword "3D-structure" "Acetylation" "Apoptosis" "Complete proteome" "Disease mutation" "Host-virus interaction" "Immunity" "Innate immunity" "Phosphoprotein" "Reference proteome") (name "FADD") (referenceDatabase [GK_2]) (secondaryIdentifier "FADD_HUMAN" "Q14866" "Q6IBR4") (sequenceLength 208) (species [GK_48887])) ([GK_54840] of ReferenceGeneProduct (_displayName "[Hsa] UniProt:P02671 FGA recommendedName: Fibrinogen alpha chain component recommendedName: Fibrinopeptide A /component component recommendedName: Fibrinogen alpha chain /component") (checksum "1") (comment "FUNCTION Fibrinogen has a double function: yielding monomers that polymerize into fibrin and acting as a cofactor in platelet aggregation.DOMAIN A long coiled coil structure formed by 3 polypeptide chains connects the central nodule to the C-terminal domains (distal nodules). The long C-terminal ends of the alpha chains fold back, contributing a fourth strand to the coiled coil structure.PTM Forms F13A-mediated cross-links between a glutamine and the epsilon-amino group of a lysine residue, forming fibronectin-fibrinogen heteropolymers.PTM Conversion of fibrinogen to fibrin is triggered by thrombin, which cleaves fibrinopeptides A and B from alpha and beta chains, and thus exposes the N-terminal polymerization sites responsible for the formation of the soft clot. The soft clot is converted into the hard clot by factor XIIIA which catalyzes the epsilon-(gamma-glutamyl)lysine cross-linking between gamma chains (stronger) and between alpha chains (weaker) of different monomers.PTM Phosphorylation sites are present in the extracelllular medium.DISEASE Defects in FGA are a cause of congenital afibrinogenemia (CAFBN) [MIM:202400]. This is a rare autosomal recessive disorder characterized by bleeding that varies from mild to severe and by complete absence or extremely low levels of plasma and platelet fibrinogen. Note=The majority of cases of afibrinogenemia are due to truncating mutations. Variations in position Arg-35 (the site of cleavage of fibrinopeptide a by thrombin) leads to alpha-dysfibrinogenemias.SIMILARITY Contains 1 fibrinogen C-terminal domain.") (DB_ID 54840) (description "recommendedName: Fibrinogen alpha chain component recommendedName: Fibrinopeptide A /component component recommendedName: Fibrinogen alpha chain /component") (geneName "FGA") (identifier "P02671") (isSequenceChanged TRUE) (keyword "3D-structure" "Alternative splicing" "Amyloid" "Amyloidosis" "Blood coagulation" "Coiled coil" "Complete proteome" "Direct protein sequencing" "Disease mutation" "Disulfide bond" "Glycoprotein" "Isopeptide bond" "Phosphoprotein" "Polymorphism" "Secreted" "Signal") (name "FGA") (referenceDatabase [GK_2]) (secondaryIdentifier "FIBA_HUMAN" "D3DP14" "D3DP15" "Q4QQH7" "Q9BX62" "Q9UCH2") (sequenceLength 866) (species [GK_48887])) ([GK_55564] of ReferenceGeneProduct (_displayName "[Hsa] UniProt:P06396 GSN recommendedName: Gelsolin alternativeName: AGEL alternativeName: Actin-depolymerizing factor shortName:ADF alternativeName: Actin-depolymerizing factor shortName:ADF alternativeName: Brevin ") (checksum "1") (comment "TISSUE SPECIFICITY Phagocytic cells, platelets, fibroblasts, nonmuscle cells, smooth and skeletal muscle cells.PTM Phosphorylation on Tyr-86, Tyr-409, Tyr-465, Tyr-603 and Tyr-651 in vitro is induced in presence of phospholipids.SIMILARITY Belongs to the villin/gelsolin family.SIMILARITY Contains 6 gelsolin-like repeats.") (DB_ID 55564) (description "recommendedName: Gelsolin alternativeName: AGEL alternativeName: Actin-depolymerizing factor shortName:ADF alternativeName: Actin-depolymerizing factor shortName:ADF alternativeName: Brevin ") (geneName "GSN") (identifier "P06396") (isSequenceChanged TRUE) (keyword "3D-structure" "Actin capping" "Actin-binding" "Alternative initiation" "Amyloid" "Amyloidosis" "Calcium" "Cilium biogenesis/degradation" "Complete proteome" "Cytoplasm" "Cytoskeleton" "Direct protein sequencing" "Disease mutation" "Disulfide bond" "Phosphoprotein" "Polymorphism" "Repeat" "Secreted" "Signal") (name "GSN") (referenceDatabase [GK_2]) (secondaryIdentifier "GELS_HUMAN" "Q8WVV7") (sequenceLength 782) (species [GK_48887])) ([GK_56134] of ReferenceGeneProduct (_displayName "[Hsa] UniProt:Q99878 HIST1H2AJ recommendedName: Histone H2A type 1-J alternativeName: Histone H2A/e ") (checksum "1") (comment "FUNCTION Core component of nucleosome. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling.SUBUNIT The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA.PTM Deiminated on Arg-4 in granulocytes upon calcium entry.PTM Phosphorylation on Ser-2 is enhanced during mitosis. Phosphorylation on Ser-2 by RPS6KA5/MSK1 directly represses transcription. Acetylation of H3 inhibits Ser-2 phosphorylation by RPS6KA5/MSK1.SIMILARITY Belongs to the histone H2A family.") (DB_ID 56134) (description "recommendedName: Histone H2A type 1-J alternativeName: Histone H2A/e ") (geneName "HIST1H2AJ" "H2AFE") (identifier "Q99878") (isSequenceChanged TRUE) (keyword "Acetylation" "Chromosome" "Citrullination" "Complete proteome" "DNA-binding" "Isopeptide bond" "Methylation" "Nucleosome core" "Nucleus" "Phosphoprotein" "Ubl conjugation") (name "HIST1H2AJ") (referenceDatabase [GK_2]) (secondaryIdentifier "H2A1J_HUMAN" "A2RUU6" "Q5JXQ5") (sequenceLength 128) (species [GK_48887])) ([GK_56136] of ReferenceGeneProduct (_displayName "[Hsa] UniProt:P20671 HIST1H2AD recommendedName: Histone H2A type 1-D alternativeName: Histone H2A.3 alternativeName: Histone H2A/g ") (checksum "1") (comment "FUNCTION Core component of nucleosome. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling.SUBUNIT The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA.PTM Deiminated on Arg-4 in granulocytes upon calcium entry.PTM Phosphorylation on Ser-2 is enhanced during mitosis. Phosphorylation on Ser-2 by RPS6KA5/MSK1 directly represses transcription. Acetylation of H3 inhibits Ser-2 phosphorylation by RPS6KA5/MSK1.SIMILARITY Belongs to the histone H2A family.CAUTION Was originally (PubMed:2587222) thought to originate from mouse.") (DB_ID 56136) (description "recommendedName: Histone H2A type 1-D alternativeName: Histone H2A.3 alternativeName: Histone H2A/g ") (geneName "HIST1H2AD" "H2AFG") (identifier "P20671") (isSequenceChanged TRUE) (keyword "Acetylation" "Chromosome" "Citrullination" "Complete proteome" "DNA-binding" "Isopeptide bond" "Methylation" "Nucleosome core" "Nucleus" "Phosphoprotein" "Ubl conjugation") (name "HIST1H2AD") (referenceDatabase [GK_2]) (secondaryIdentifier "H2A1D_HUMAN" "A0PK91" "P57754" "Q6FGY6") (sequenceLength 130) (species [GK_48887])) ([GK_56140] of ReferenceGeneProduct (_displayName "[Hsa] UniProt:Q93077 HIST1H2AC recommendedName: Histone H2A type 1-C alternativeName: Histone H2A/l ") (checksum "1") (comment "FUNCTION Core component of nucleosome. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling.SUBUNIT The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA.PTM Deiminated on Arg-4 in granulocytes upon calcium entry.PTM Phosphorylation on Ser-2 is enhanced during mitosis. Phosphorylation on Ser-2 by RPS6KA5/MSK1 directly represses transcription. Acetylation of H3 inhibits Ser-2 phosphorylation by RPS6KA5/MSK1.SIMILARITY Belongs to the histone H2A family.") (DB_ID 56140) (description "recommendedName: Histone H2A type 1-C alternativeName: Histone H2A/l ") (geneName "HIST1H2AC" "H2AFL") (identifier "Q93077") (isSequenceChanged TRUE) (keyword "Acetylation" "Chromosome" "Citrullination" "Complete proteome" "DNA-binding" "Isopeptide bond" "Methylation" "Nucleosome core" "Nucleus" "Phosphoprotein" "Ubl conjugation") (name "HIST1H2AC") (referenceDatabase [GK_2]) (secondaryIdentifier "H2A1C_HUMAN" "B2R4F7" "O00775" "O00776" "O00777" "O00778" "Q540R1") (sequenceLength 130) (species [GK_48887])) ([GK_56142] of ReferenceGeneProduct (_displayName "[Hsa] UniProt:P04908 HIST1H2AB recommendedName: Histone H2A type 1-B/E alternativeName: Histone H2A.2 alternativeName: Histone H2A/a alternativeName: Histone H2A/m ") (checksum "1") (comment "FUNCTION Core component of nucleosome. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling.SUBUNIT The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA.PTM Deiminated on Arg-4 in granulocytes upon calcium entry.PTM Phosphorylation on Ser-2 is enhanced during mitosis. Phosphorylation on Ser-2 by RPS6KA5/MSK1 directly represses transcription. Acetylation of H3 inhibits Ser-2 phosphorylation by RPS6KA5/MSK1.SIMILARITY Belongs to the histone H2A family.") (DB_ID 56142) (description "recommendedName: Histone H2A type 1-B/E alternativeName: Histone H2A.2 alternativeName: Histone H2A/a alternativeName: Histone H2A/m ") (geneName "HIST1H2AB" "H2AFM" "" "" "HIST1H2AE" "H2AFA") (identifier "P04908") (isSequenceChanged TRUE) (keyword "3D-structure" "Acetylation" "Chromosome" "Citrullination" "Complete proteome" "DNA-binding" "Isopeptide bond" "Methylation" "Nucleosome core" "Nucleus" "Phosphoprotein" "Ubl conjugation") (name "HIST1H2AB") (referenceDatabase [GK_2]) (secondaryIdentifier "H2A1B_HUMAN" "P28001" "Q76P63") (sequenceLength 130) (species [GK_48887])) ([GK_56148] of ReferenceGeneProduct (_displayName "[Hsa] UniProt:Q16777 HIST2H2AC recommendedName: Histone H2A type 2-C alternativeName: Histone H2A-GL101 alternativeName: Histone H2A/q ") (checksum "1") (comment "FUNCTION Core component of nucleosome. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling.SUBUNIT The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA.PTM Deiminated on Arg-4 in granulocytes upon calcium entry.PTM Phosphorylation on Ser-2 is enhanced during mitosis. Phosphorylation on Ser-2 by RPS6KA5/MSK1 directly represses transcription. Acetylation of H3 inhibits Ser-2 phosphorylation by RPS6KA5/MSK1.SIMILARITY Belongs to the histone H2A family.") (DB_ID 56148) (description "recommendedName: Histone H2A type 2-C alternativeName: Histone H2A-GL101 alternativeName: Histone H2A/q ") (geneName "HIST2H2AC" "H2AFQ") (identifier "Q16777") (isSequenceChanged TRUE) (keyword "Acetylation" "Chromosome" "Citrullination" "Complete proteome" "DNA-binding" "Isopeptide bond" "Methylation" "Nucleosome core" "Nucleus" "Phosphoprotein" "Ubl conjugation") (name "HIST2H2AC") (referenceDatabase [GK_2]) (secondaryIdentifier "H2A2C_HUMAN" "Q6DRA7" "Q8IUE5") (sequenceLength 129) (species [GK_48887])) ([GK_56152] of ReferenceGeneProduct (_displayName "[Hsa] UniProt:P16104 H2AFX recommendedName: Histone H2A.x shortName:H2a/x ") (checksum "1") (comment "DEVELOPMENTAL STAGE Synthesized in G1 as well as in S-phase.DOMAIN The [ST]-Q motif constitutes a recognition sequence for kinases from the PI3/PI4-kinase family.PTM Monoubiquitination of Lys-120 (H2AXK119ub) by RING1 and RNF2/RING2 complex gives a specific tag for epigenetic transcriptional repression. Following DNA double-strand breaks (DSBs), it is ubiquitinated through 'Lys-63' linkage of ubiquitin moieties by the E2 ligase UBE2N and the E3 ligases RNF8 and RNF168, leading to the recruitment of repair proteins to sites of DNA damage. Monoubiquitination and ionizing radiation-induced 'Lys-63'-linked ubiquitination are distinct events.SIMILARITY Belongs to the histone H2A family.") (DB_ID 56152) (description "recommendedName: Histone H2A.x shortName:H2a/x ") (geneName "H2AFX" "H2AX") (identifier "P16104") (isSequenceChanged TRUE) (keyword "3D-structure" "Acetylation" "Cell cycle" "Chromosome" "Complete proteome" "DNA damage" "DNA recombination" "DNA repair" "DNA-binding" "Isopeptide bond" "Meiosis" "Nucleosome core" "Nucleus" "Phosphoprotein" "Ubl conjugation") (name "H2AFX") (referenceDatabase [GK_2]) (secondaryIdentifier "H2AX_HUMAN" "Q4ZGJ7" "Q6IAS5") (sequenceLength 143) (species [GK_48887])) ([GK_56164] of ReferenceGeneProduct (_displayName "[Hsa] UniProt:P62807 HIST1H2BC recommendedName: Histone H2B type 1-C/E/F/G/I alternativeName: Histone H2B.1 A alternativeName: Histone H2B.a shortName:H2B/a alternativeName: Histone H2B.a shortName:H2B/a alternativeName: Histone H2B.g shortName:H2B/g alternativeName: Histone H2B.g shortName:H2B/g alternativeName: Histone H2B.h shortName:H2B/h alternativeName: Histone H2B.h shortName:H2B/h alternativeName: Histone H2B.k shortName:H2B/k alternativeName: Histone H2B.k shortName:H2B/k alternativeName: Histone H2B.l shortName:H2B/l alternativeName: Histone H2B.l shortName:H2B/l ") (checksum "1") (comment "SUBUNIT The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA.PTM Monoubiquitination of Lys-121 by the RNF20/40 complex gives a specific tag for epigenetic transcriptional activation and is also prerequisite for histone H3 'Lys-4' and 'Lys-79' methylation. It also functions cooperatively with the FACT dimer to stimulate elongation by RNA polymerase II.SIMILARITY Belongs to the histone H2B family.") (DB_ID 56164) (description "recommendedName: Histone H2B type 1-C/E/F/G/I alternativeName: Histone H2B.1 A alternativeName: Histone H2B.a shortName:H2B/a alternativeName: Histone H2B.a shortName:H2B/a alternativeName: Histone H2B.g shortName:H2B/g alternativeName: Histone H2B.g shortName:H2B/g alternativeName: Histone H2B.h shortName:H2B/h alternativeName: Histone H2B.h shortName:H2B/h alternativeName: Histone H2B.k shortName:H2B/k alternativeName: Histone H2B.k shortName:H2B/k alternativeName: Histone H2B.l shortName:H2B/l alternativeName: Histone H2B.l shortName:H2B/l ") (geneName "HIST1H2BC" "H2BFL" "" "" "HIST1H2BE" "H2BFH" "" "" "HIST1H2BF" "H2BFG" "" "" "HIST1H2BG" "H2BFA" "" "" "HIST1H2BI" "H2BFK") (identifier "P62807") (isSequenceChanged TRUE) (keyword "Acetylation" "Antibiotic" "Antimicrobial" "Chromosome" "Complete proteome" "Direct protein sequencing" "DNA-binding" "Isopeptide bond" "Methylation" "Nucleosome core" "Nucleus" "Phosphoprotein" "Polymorphism" "Ubl conjugation") (name "HIST1H2BC") (referenceDatabase [GK_2]) (secondaryIdentifier "H2B1C_HUMAN" "P02278" "Q3B872" "Q4VB69" "Q93078" "Q93080") (sequenceLength 126) (species [GK_48887])) ([GK_56168] of ReferenceGeneProduct (_displayName "[Hsa] UniProt:P58876 HIST1H2BD recommendedName: Histone H2B type 1-D alternativeName: HIRA-interacting protein 2 alternativeName: Histone H2B.1 B alternativeName: Histone H2B.b shortName:H2B/b alternativeName: Histone H2B.b shortName:H2B/b ") (checksum "1") (comment "FUNCTION Core component of nucleosome. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling.SUBUNIT The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA.PTM Monoubiquitination of Lys-121 by the RNF20/40 complex gives a specific tag for epigenetic transcriptional activation and is also prerequisite for histone H3 'Lys-4' and 'Lys-79' methylation. It also functions cooperatively with the FACT dimer to stimulate elongation by RNA polymerase II.MISCELLANEOUS The mouse orthologous protein seems not to exist.SIMILARITY Belongs to the histone H2B family.") (DB_ID 56168) (description "recommendedName: Histone H2B type 1-D alternativeName: HIRA-interacting protein 2 alternativeName: Histone H2B.1 B alternativeName: Histone H2B.b shortName:H2B/b alternativeName: Histone H2B.b shortName:H2B/b ") (geneName "HIST1H2BD" "H2BFB" "HIRIP2") (identifier "P58876") (isSequenceChanged TRUE) (keyword "Acetylation" "Chromosome" "Complete proteome" "Direct protein sequencing" "DNA-binding" "Isopeptide bond" "Methylation" "Nucleosome core" "Nucleus" "Phosphoprotein" "Ubl conjugation") (name "HIST1H2BD") (referenceDatabase [GK_2]) (secondaryIdentifier "H2B1D_HUMAN") (sequenceLength 126) (species [GK_48887])) ([GK_56170] of ReferenceGeneProduct (_displayName "[Hsa] UniProt:Q99880 HIST1H2BL recommendedName: Histone H2B type 1-L alternativeName: Histone H2B.c shortName:H2B/c alternativeName: Histone H2B.c shortName:H2B/c ") (checksum "1") (comment "FUNCTION Core component of nucleosome. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling.SUBUNIT The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA.PTM Monoubiquitination of Lys-121 by the RNF20/40 complex gives a specific tag for epigenetic transcriptional activation and is also prerequisite for histone H3 'Lys-4' and 'Lys-79' methylation. It also functions cooperatively with the FACT dimer to stimulate elongation by RNA polymerase II.SIMILARITY Belongs to the histone H2B family.") (DB_ID 56170) (description "recommendedName: Histone H2B type 1-L alternativeName: Histone H2B.c shortName:H2B/c alternativeName: Histone H2B.c shortName:H2B/c ") (geneName "HIST1H2BL" "H2BFC") (identifier "Q99880") (isSequenceChanged TRUE) (keyword "Acetylation" "Chromosome" "Complete proteome" "Direct protein sequencing" "DNA-binding" "Isopeptide bond" "Methylation" "Nucleosome core" "Nucleus" "Phosphoprotein" "Polymorphism" "Ubl conjugation") (name "HIST1H2BL") (referenceDatabase [GK_2]) (secondaryIdentifier "H2B1L_HUMAN" "B2R5A3" "Q52LW9") (sequenceLength 126) (species [GK_48887])) ([GK_56172] of ReferenceGeneProduct (_displayName "[Hsa] UniProt:Q99877 HIST1H2BN recommendedName: Histone H2B type 1-N alternativeName: Histone H2B.d shortName:H2B/d alternativeName: Histone H2B.d shortName:H2B/d ") (checksum "1") (comment "FUNCTION Core component of nucleosome. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling.SUBUNIT The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA.PTM Monoubiquitination of Lys-121 by the RNF20/40 complex gives a specific tag for epigenetic transcriptional activation and is also prerequisite for histone H3 'Lys-4' and 'Lys-79' methylation. It also functions cooperatively with the FACT dimer to stimulate elongation by RNA polymerase II.SIMILARITY Belongs to the histone H2B family.") (DB_ID 56172) (description "recommendedName: Histone H2B type 1-N alternativeName: Histone H2B.d shortName:H2B/d alternativeName: Histone H2B.d shortName:H2B/d ") (geneName "HIST1H2BN" "H2BFD") (identifier "Q99877") (isSequenceChanged TRUE) (keyword "Acetylation" "Chromosome" "Complete proteome" "Direct protein sequencing" "DNA-binding" "Isopeptide bond" "Methylation" "Nucleosome core" "Nucleus" "Phosphoprotein" "Ubl conjugation") (name "HIST1H2BN") (referenceDatabase [GK_2]) (secondaryIdentifier "H2B1N_HUMAN" "B2R5L4" "Q494S8" "Q96FB7") (sequenceLength 126) (species [GK_48887])) ([GK_56174] of ReferenceGeneProduct (_displayName "[Hsa] UniProt:Q99879 HIST1H2BM recommendedName: Histone H2B type 1-M alternativeName: Histone H2B.e shortName:H2B/e alternativeName: Histone H2B.e shortName:H2B/e ") (checksum "1") (comment "FUNCTION Core component of nucleosome. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling.SUBUNIT The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA.PTM Monoubiquitination of Lys-121 by the RNF20/40 complex gives a specific tag for epigenetic transcriptional activation and is also prerequisite for histone H3 'Lys-4' and 'Lys-79' methylation. It also functions cooperatively with the FACT dimer to stimulate elongation by RNA polymerase II.SIMILARITY Belongs to the histone H2B family.") (DB_ID 56174) (description "recommendedName: Histone H2B type 1-M alternativeName: Histone H2B.e shortName:H2B/e alternativeName: Histone H2B.e shortName:H2B/e ") (geneName "HIST1H2BM" "H2BFE") (identifier "Q99879") (isSequenceChanged TRUE) (keyword "Acetylation" "Chromosome" "Complete proteome" "Direct protein sequencing" "DNA-binding" "Isopeptide bond" "Methylation" "Nucleosome core" "Nucleus" "Phosphoprotein" "Polymorphism" "Ubl conjugation") (name "HIST1H2BM") (referenceDatabase [GK_2]) (secondaryIdentifier "H2B1M_HUMAN" "Q6NWQ3") (sequenceLength 126) (species [GK_48887])) ([GK_56176] of ReferenceGeneProduct (_displayName "[Hsa] UniProt:P33778 HIST1H2BB recommendedName: Histone H2B type 1-B alternativeName: Histone H2B.1 alternativeName: Histone H2B.f shortName:H2B/f alternativeName: Histone H2B.f shortName:H2B/f ") (checksum "1") (comment "FUNCTION Core component of nucleosome. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling.SUBUNIT The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA.PTM Monoubiquitination of Lys-121 by the RNF20/40 complex gives a specific tag for epigenetic transcriptional activation and is also prerequisite for histone H3 'Lys-4' and 'Lys-79' methylation. It also functions cooperatively with the FACT dimer to stimulate elongation by RNA polymerase II.SIMILARITY Belongs to the histone H2B family.") (DB_ID 56176) (description "recommendedName: Histone H2B type 1-B alternativeName: Histone H2B.1 alternativeName: Histone H2B.f shortName:H2B/f alternativeName: Histone H2B.f shortName:H2B/f ") (geneName "HIST1H2BB" "H2BFF") (identifier "P33778") (isSequenceChanged TRUE) (keyword "Acetylation" "Chromosome" "Complete proteome" "DNA-binding" "Isopeptide bond" "Methylation" "Nucleosome core" "Nucleus" "Phosphoprotein" "Ubl conjugation") (name "HIST1H2BB") (referenceDatabase [GK_2]) (secondaryIdentifier "H2B1B_HUMAN" "Q4KN36") (sequenceLength 126) (species [GK_48887])) ([GK_56180] of ReferenceGeneProduct (_displayName "[Hsa] UniProt:Q93079 HIST1H2BH recommendedName: Histone H2B type 1-H alternativeName: Histone H2B.j shortName:H2B/j alternativeName: Histone H2B.j shortName:H2B/j ") (checksum "1") (comment "FUNCTION Core component of nucleosome. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling.SUBUNIT The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA.PTM Monoubiquitination of Lys-121 by the RNF20/40 complex gives a specific tag for epigenetic transcriptional activation and is also prerequisite for histone H3 'Lys-4' and 'Lys-79' methylation. It also functions cooperatively with the FACT dimer to stimulate elongation by RNA polymerase II.SIMILARITY Belongs to the histone H2B family.") (DB_ID 56180) (description "recommendedName: Histone H2B type 1-H alternativeName: Histone H2B.j shortName:H2B/j alternativeName: Histone H2B.j shortName:H2B/j ") (geneName "HIST1H2BH" "H2BFJ") (identifier "Q93079") (isSequenceChanged TRUE) (keyword "Acetylation" "Chromosome" "Complete proteome" "Direct protein sequencing" "DNA-binding" "Isopeptide bond" "Methylation" "Nucleosome core" "Nucleus" "Phosphoprotein" "Ubl conjugation") (name "HIST1H2BH") (referenceDatabase [GK_2]) (secondaryIdentifier "H2B1H_HUMAN" "B2R541" "Q4VB74") (sequenceLength 126) (species [GK_48887])) ([GK_56184] of ReferenceGeneProduct (_displayName "[Hsa] UniProt:P23527 HIST1H2BO recommendedName: Histone H2B type 1-O alternativeName: Histone H2B.2 alternativeName: Histone H2B.n shortName:H2B/n alternativeName: Histone H2B.n shortName:H2B/n ") (checksum "1") (comment "FUNCTION Core component of nucleosome. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling.SUBUNIT The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA.PTM Monoubiquitination of Lys-121 by the RNF20/40 complex gives a specific tag for epigenetic transcriptional activation and is also prerequisite for histone H3 'Lys-4' and 'Lys-79' methylation. It also functions cooperatively with the FACT dimer to stimulate elongation by RNA polymerase II.MISCELLANEOUS The mouse orthologous protein seems not to exist.SIMILARITY Belongs to the histone H2B family.") (DB_ID 56184) (description "recommendedName: Histone H2B type 1-O alternativeName: Histone H2B.2 alternativeName: Histone H2B.n shortName:H2B/n alternativeName: Histone H2B.n shortName:H2B/n ") (geneName "HIST1H2BO" "H2BFH" "H2BFN") (identifier "P23527") (isSequenceChanged TRUE) (keyword "Acetylation" "Chromosome" "Complete proteome" "Direct protein sequencing" "DNA-binding" "Isopeptide bond" "Methylation" "Nucleosome core" "Nucleus" "Phosphoprotein" "Ubl conjugation") (name "HIST1H2BO") (referenceDatabase [GK_2]) (secondaryIdentifier "H2B1O_HUMAN" "Q3KPI7" "Q8TCV6") (sequenceLength 126) (species [GK_48887])) ([GK_56186] of ReferenceGeneProduct (_displayName "[Hsa] UniProt:Q16778 HIST2H2BE recommendedName: Histone H2B type 2-E alternativeName: Histone H2B-GL105 alternativeName: Histone H2B.q shortName:H2B/q alternativeName: Histone H2B.q shortName:H2B/q ") (checksum "1") (comment "SUBUNIT The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA.PTM Monoubiquitination of Lys-121 by the RNF20/40 complex gives a specific tag for epigenetic transcriptional activation and is also prerequisite for histone H3 'Lys-4' and 'Lys-79' methylation. It also functions cooperatively with the FACT dimer to stimulate elongation by RNA polymerase II.SIMILARITY Belongs to the histone H2B family.") (DB_ID 56186) (description "recommendedName: Histone H2B type 2-E alternativeName: Histone H2B-GL105 alternativeName: Histone H2B.q shortName:H2B/q alternativeName: Histone H2B.q shortName:H2B/q ") (geneName "HIST2H2BE" "H2BFQ") (identifier "Q16778") (isSequenceChanged TRUE) (keyword "Acetylation" "Antibiotic" "Antimicrobial" "Chromosome" "Complete proteome" "Direct protein sequencing" "DNA-binding" "Isopeptide bond" "Methylation" "Nucleosome core" "Nucleus" "Phosphoprotein" "Ubl conjugation") (name "HIST2H2BE") (referenceDatabase [GK_2]) (secondaryIdentifier "H2B2E_HUMAN" "A3KMC7" "A8K110" "Q4KMY1" "Q5QNX0" "Q9UE88") (sequenceLength 126) (species [GK_48887])) ([GK_56188] of ReferenceGeneProduct (_displayName "[Hsa] UniProt:P06899 HIST1H2BJ recommendedName: Histone H2B type 1-J alternativeName: Histone H2B.1 alternativeName: Histone H2B.r shortName:H2B/r alternativeName: Histone H2B.r shortName:H2B/r ") (checksum "1") (comment "SUBUNIT The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA.PTM Monoubiquitination of Lys-121 by the RNF20/40 complex gives a specific tag for epigenetic transcriptional activation and is also prerequisite for histone H3 'Lys-4' and 'Lys-79' methylation. It also functions cooperatively with the FACT dimer to stimulate elongation by RNA polymerase II.SIMILARITY Belongs to the histone H2B family.") (DB_ID 56188) (description "recommendedName: Histone H2B type 1-J alternativeName: Histone H2B.1 alternativeName: Histone H2B.r shortName:H2B/r alternativeName: Histone H2B.r shortName:H2B/r ") (geneName "HIST1H2BJ" "H2BFR") (identifier "P06899") (isSequenceChanged TRUE) (keyword "3D-structure" "Acetylation" "Antibiotic" "Antimicrobial" "Chromosome" "Complete proteome" "Direct protein sequencing" "DNA-binding" "Isopeptide bond" "Methylation" "Nucleosome core" "Nucleus" "Phosphoprotein" "Ubl conjugation") (name "HIST1H2BJ") (referenceDatabase [GK_2]) (secondaryIdentifier "H2B1J_HUMAN" "B2R4J4" "O60816") (sequenceLength 126) (species [GK_48887])) ([GK_56190] of ReferenceGeneProduct (_displayName "[Hsa] UniProt:P57053 H2BFS recommendedName: Histone H2B type F-S alternativeName: Histone H2B.s shortName:H2B/s alternativeName: Histone H2B.s shortName:H2B/s ") (checksum "1") (comment "SUBUNIT The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA.PTM Monoubiquitination of Lys-121 by the RNF20/40 complex gives a specific tag for epigenetic transcriptional activation and is also prerequisite for histone H3 'Lys-4' and 'Lys-79' methylation. It also functions cooperatively with the FACT dimer to stimulate elongation by RNA polymerase II.SIMILARITY Belongs to the histone H2B family.") (DB_ID 56190) (description "recommendedName: Histone H2B type F-S alternativeName: Histone H2B.s shortName:H2B/s alternativeName: Histone H2B.s shortName:H2B/s ") (geneName "H2BFS") (identifier "P57053") (isSequenceChanged TRUE) (keyword "Acetylation" "Antibiotic" "Antimicrobial" "Chromosome" "Complete proteome" "Direct protein sequencing" "DNA-binding" "Isopeptide bond" "Methylation" "Nucleosome core" "Nucleus" "Phosphoprotein" "Ubl conjugation") (name "H2BFS") (referenceDatabase [GK_2]) (secondaryIdentifier "H2BFS_HUMAN" "A0AVF9" "Q5R2W0") (sequenceLength 126) (species [GK_48887])) ([GK_56978] of ReferenceGeneProduct (_displayName "[Hsa] UniProt:P10997 IAPP recommendedName: Islet amyloid polypeptide alternativeName: Amylin alternativeName: Diabetes-associated peptide shortName:DAP alternativeName: Diabetes-associated peptide shortName:DAP alternativeName: Insulinoma amyloid peptide ") (checksum "1") (comment "FUNCTION Selectively inhibits insulin-stimulated glucose utilization and glycogen deposition in muscle, while not affecting adipocyte glucose metabolism.PTM Amyloid fibrils are degraded by IDE.MISCELLANEOUS IAPP is the peptide subunit of amyloid found in pancreatic islets of type 2 diabetic patients and in insulinomas.SIMILARITY Belongs to the calcitonin family.") (DB_ID 56978) (description "recommendedName: Islet amyloid polypeptide alternativeName: Amylin alternativeName: Diabetes-associated peptide shortName:DAP alternativeName: Diabetes-associated peptide shortName:DAP alternativeName: Insulinoma amyloid peptide ") (geneName "IAPP") (identifier "P10997") (isSequenceChanged TRUE) (keyword "3D-structure" "Amidation" "Amyloid" "Cleavage on pair of basic residues" "Complete proteome" "Direct protein sequencing" "Disulfide bond" "Hormone" "Polymorphism" "Secreted" "Signal") (name "IAPP") (referenceDatabase [GK_2]) (secondaryIdentifier "IAPP_HUMAN" "Q0ZD87" "Q14598") (sequenceLength 89) (species [GK_48887])) ([GK_57031] of EntityWithAccessionedSequence (_displayName "[Hsa] Caspase-8 precursor [cytosol]") (compartment [GK_70101]) (DB_ID 57031) (endCoordinate 374) (name "Caspase-8 precursor " "ICE-like apoptotic protease 5" "MORT1-associated CED-3 homolog" "MACH" "FADD-homologous ICE/CED-3- like protease" "FADD-like ICE" "FLICE" "Apoptotic cysteine protease" "Apoptotic protease Mch-5" "CAP4") (referenceEntity [GK_57032]) (species [GK_48887]) (stableIdentifier [GK_362980]) (startCoordinate 217)) ([GK_57032] of ReferenceGeneProduct (_displayName "[Hsa] UniProt:Q14790 CASP8 recommendedName: Caspase-8 shortName:CASP-8 ecNumber3.4.22.61/ecNumber alternativeName: Apoptotic cysteine protease alternativeName: Apoptotic protease Mch-5 alternativeName: CAP4 alternativeName: FADD-homologous ICE/ced-3-like protease alternativeName: FADD-like ICE shortName:FLICE alternativeName: ICE-like apoptotic protease 5 alternativeName: MORT1-associated ced-3 homolog shortName:MACH component recommendedName: Caspase-8 subunit p18 /component component recommendedName: Caspase-8 subunit p10 /component") (checksum "7A5FEAA6B39B582F") (comment "FUNCTION Most upstream protease of the activation cascade of caspases responsible for the TNFRSF6/FAS mediated and TNFRSF1A induced cell death. Binding to the adapter molecule FADD recruits it to either receptor. The resulting aggregate called death-inducing signaling complex (DISC) performs CASP8 proteolytic activation. The active dimeric enzyme is then liberated from the DISC and free to activate downstream apoptotic proteases. Proteolytic fragments of the N-terminal propeptide (termed CAP3, CAP5 and CAP6) are likely retained in the DISC. Cleaves and activates CASP3, CASP4, CASP6, CASP7, CASP9 and CASP10. May participate in the GZMB apoptotic pathways. Cleaves ADPRT. Hydrolyzes the small-molecule substrate, Ac-Asp-Glu-Val-Asp-|-AMC. Likely target for the cowpox virus CRMA death inhibitory protein. Isoform 5, isoform 6, isoform 7 and isoform 8 lack the catalytic site and may interfere with the pro-apoptotic activity of the complex.CATALYTIC ACTIVITY Strict requirement for Asp at position P1 and has a preferred cleavage sequence of (Leu/Asp/Val)-Glu-Thr-Asp-|-(Gly/Ser/Ala).SUBUNIT Heterotetramer that consists of two anti-parallel arranged heterodimers, each one formed by a 18 kDa (p18) and a 10 kDa (p10) subunit. Interacts with FADD, CFLAR and PEA15. Isoform 9 interacts at the endoplasmic reticulum with a complex containing BCAP31, BAP29, BCL2 and/or BCL2L1. Interacts with TNFAIP8L2 (By similarity). Interacts with human cytomegalovirus/HHV-5 protein vICA/UL36; this interaction inhibits CASP8 activation.TISSUE SPECIFICITY Isoform 1, isoform 5 and isoform 7 are expressed in a wide variety of tissues. Highest expression in peripheral blood leukocytes, spleen, thymus and liver. Barely detectable in brain, testis and skeletal muscle.DOMAIN Isoform 9 contains a N-terminal extension that is required for interaction with the BCAP31 complex.PTM Generation of the subunits requires association with the death-inducing signaling complex (DISC), whereas additional processing is likely due to the autocatalytic activity of the activated protease. GZMB and CASP10 can be involved in these processing events.PTM Phosphorylated upon DNA damage, probably by ATM or ATR. Phosphorylation on Ser-387 during mitosis by CDK1 inhibits activation by proteolysis and prevents apoptosis. This phosphorylation occurs in cancer cell lines, as well as in primary breast tissues and lymphocytes.POLYMORPHISM Genetic variations in CASP8 are associated with reduced risk of lung cancer [MIM:211980] in a population of Han Chinese subjects. Genetic variations are also associated with decreased risk of cancer of various other forms including esophageal, gastric, colorectal, cervical, and breast, acting in an allele dose-dependent manner.DISEASE Defects in CASP8 are the cause of caspase-8 deficiency (CASP8D) [MIM:607271]. CASP8D is a disorder resembling autoimmune lymphoproliferative syndrome (ALPS). It is characterized by lymphadenopathy, splenomegaly, and defective CD95-induced apoptosis of peripheral blood lymphocytes (PBLs). It leads to defects in activation of T-lymphocytes, B-lymphocytes, and natural killer cells leading to immunodeficiency characterized by recurrent sinopulmonary and herpes simplex virus infections and poor responses to immunization.SIMILARITY Belongs to the peptidase C14A family.SIMILARITY Contains 2 DED (death effector) domains.") (DB_ID 57032) (description "recommendedName: Caspase-8 shortName:CASP-8 ecNumber3.4.22.61/ecNumber alternativeName: Apoptotic cysteine protease alternativeName: Apoptotic protease Mch-5 alternativeName: CAP4 alternativeName: FADD-homologous ICE/ced-3-like protease alternativeName: FADD-like ICE shortName:FLICE alternativeName: ICE-like apoptotic protease 5 alternativeName: MORT1-associated ced-3 homolog shortName:MACH component recommendedName: Caspase-8 subunit p18 /component component recommendedName: Caspase-8 subunit p10 /component") (geneName "CASP8" "MCH5") (identifier "Q14790") (isSequenceChanged FALSE) (keyword "3D-structure" "Alternative splicing" "Apoptosis" "Complete proteome" "Cytoplasm" "Direct protein sequencing" "Disease mutation" "Host-virus interaction" "Hydrolase" "Phosphoprotein" "Polymorphism" "Protease" "Reference proteome" "Repeat" "Thiol protease" "Zymogen") (name "CASP8") (referenceDatabase [GK_2]) (secondaryIdentifier "CASP8_HUMAN" "O14676" "Q14791" "Q14792" "Q14793" "Q14794" "Q14795" "Q14796" "Q15780" "Q15806" "Q53TT5" "Q8TDI1" "Q8TDI2" "Q8TDI3" "Q8TDI4" "Q8TDI5" "Q96T22" "Q9C0K4" "Q9UQ81") (sequenceLength 479) (species [GK_48887])) ([GK_57035] of EntityWithAccessionedSequence (_displayName "[Hsa] Caspase-10 precursor [plasma membrane]") (compartment [GK_876]) (DB_ID 57035) (endCoordinate 415) (name "Caspase-10 precursor " "ICE-like apoptotic protease 4" "Apoptotic protease Mch-4" "FAS-associated death domain protein interleukin-1B-converting enzyme 2" "FLICE2") (referenceEntity [GK_57036]) (species [GK_48887]) (stableIdentifier [GK_370163]) (startCoordinate 220)) ([GK_57036] of ReferenceGeneProduct (_displayName "[Hsa] UniProt:Q92851 CASP10 recommendedName: Caspase-10 shortName:CASP-10 ecNumber3.4.22.63/ecNumber alternativeName: Apoptotic protease Mch-4 alternativeName: FAS-associated death domain protein interleukin-1B-converting enzyme 2 shortName:FLICE2 alternativeName: ICE-like apoptotic protease 4 component recommendedName: Caspase-10 subunit p23/17 /component component recommendedName: Caspase-10 subunit p12 /component") (checksum "840348AE602B8243") (comment "FUNCTION Involved in the activation cascade of caspases responsible for apoptosis execution. Recruited to both Fas- and TNFR-1 receptors in a FADD dependent manner. May participate in the granzyme B apoptotic pathways. Cleaves and activates caspase-3, -4, -6, -7, -8, and -9. Hydrolyzes the small- molecule substrates, Tyr-Val-Ala-Asp-|-AMC and Asp-Glu-Val-Asp-|-AMC.FUNCTION Isoform C is proteolytically inactive.CATALYTIC ACTIVITY Strict requirement for Asp at position P1 and has a preferred cleavage sequence of Leu-Gln-Thr-Asp-|-Gly.SUBUNIT Heterotetramer that consists of two anti-parallel arranged heterodimers, each one formed by a 23/17 kDa (p23/17) (depending on the splicing events) and a 12 kDa (p12) subunit (By similarity). Self-associates. Interacts with FADD and CASP8. Found in a Fas signaling complex consisting of FAS, FADD, CASP8 and CASP10.TISSUE SPECIFICITY Detectable in most tissues. Lowest expression is seen in brain, kidney, prostate, testis and colon.PTM Cleavage by granzyme B and autocatalytic activity generate the two active subunits.PTM Phosphorylated upon DNA damage, probably by ATM or ATR.DISEASE Defects in CASP10 are the cause of autoimmune lymphoproliferative syndrome type 2A (ALPS2A) [MIM:603909]. ALPS2 is characterized by abnormal lymphocyte and dendritic cell homeostasis and immune regulatory defects.DISEASE Defects in CASP10 are a cause of familial non-Hodgkin lymphoma (NHL) [MIM:605027]. NHL is a cancer that starts in cells of the lymph system, which is part of the body's immune system. NHLs can occur at any age and are often marked by enlarged lymph nodes, fever and weight loss.DISEASE Defects in CASP10 are a cause of gastric cancer (GASC) [MIM:613659]. A malignant disease which starts in the stomach, can spread to the esophagus or the small intestine, and can extend through the stomach wall to nearby lymph nodes and organs. It also can metastasize to other parts of the body. The term gastric cancer or gastric carcinoma refers to adenocarcinoma of the stomach that accounts for most of all gastric malignant tumors. Two main histologic types are recognized, diffuse type and intestinal type carcinomas. Diffuse tumors are poorly differentiated infiltrating lesions resulting in thickening of the stomach. In contrast, intestinal tumors are usually exophytic, often ulcerating, and associated with intestinal metaplasia of the stomach, most often observed in sporadic disease.SIMILARITY Belongs to the peptidase C14A family.SIMILARITY Contains 2 DED (death effector) domains.") (DB_ID 57036) (description "recommendedName: Caspase-10 shortName:CASP-10 ecNumber3.4.22.63/ecNumber alternativeName: Apoptotic protease Mch-4 alternativeName: FAS-associated death domain protein interleukin-1B-converting enzyme 2 shortName:FLICE2 alternativeName: ICE-like apoptotic protease 4 component recommendedName: Caspase-10 subunit p23/17 /component component recommendedName: Caspase-10 subunit p12 /component") (geneName "CASP10" "MCH4") (identifier "Q92851") (isSequenceChanged TRUE) (keyword "Alternative splicing" "Apoptosis" "Complete proteome" "Direct protein sequencing" "Disease mutation" "Hydrolase" "Phosphoprotein" "Polymorphism" "Protease" "Reference proteome" "Repeat" "Thiol protease" "Zymogen") (name "CASP10") (referenceDatabase [GK_2]) (secondaryIdentifier "CASPA_HUMAN" "Q6KF62" "Q6KF63" "Q8IUP5" "Q8WYQ8" "Q99845" "Q9Y2U6" "Q9Y2U7") (sequenceLength 521) (species [GK_48887])) ([GK_571213] of Person (_displayName "Zhou, H") (DB_ID 571213) (firstname "Huaijun") (initial "H") (surname "Zhou")) ([GK_57415] of ReferenceGeneProduct (_displayName "[Hsa] UniProt:P01308 INS recommendedName: Insulin component recommendedName: Insulin B chain /component component recommendedName: Insulin A chain /component") (checksum "1") (comment "FUNCTION Insulin decreases blood glucose concentration. It increases cell permeability to monosaccharides, amino acids and fatty acids. It accelerates glycolysis, the pentose phosphate cycle, and glycogen synthesis in liver.SUBUNIT Heterodimer of a B chain and an A chain linked by two disulfide bonds.PHARMACEUTICAL Available under the names Humulin or Humalog (Eli Lilly) and Novolin (Novo Nordisk). Used in the treatment of diabetes. Humalog is an insulin analog with 52-Lys-Pro-53 instead of 52-Pro-Lys-53.SIMILARITY Belongs to the insulin family.") (DB_ID 57415) (description "recommendedName: Insulin component recommendedName: Insulin B chain /component component recommendedName: Insulin A chain /component") (geneName "INS") (identifier "P01308") (isSequenceChanged TRUE) (keyword "3D-structure" "Carbohydrate metabolism" "Cleavage on pair of basic residues" "Complete proteome" "Diabetes mellitus" "Direct protein sequencing" "Disease mutation" "Disulfide bond" "Glucose metabolism" "Hormone" "Pharmaceutical" "Polymorphism" "Secreted" "Signal") (name "INS") (referenceDatabase [GK_2]) (secondaryIdentifier "INS_HUMAN" "Q5EEX2") (sequenceLength 110) (species [GK_48887])) ([GK_57627] of ReferenceGeneProduct (_displayName "[Hsa] UniProt:Q9Y287 ITM2B recommendedName: Integral membrane protein 2B alternativeName: Protein E25B alternativeName: Transmembrane protein BRI component recommendedName: ABri/ADan amyloid peptide /component") (checksum "1") (comment "TISSUE SPECIFICITY Expressed in brain and in other tissues.DISEASE Defects in ITM2B are a cause of cerebral amyloid angiopathy ITM2B-related type 2 (CAA-ITM2B2) [MIM:117300]; also known as heredopathia ophthalmo-oto-encephalica. A disorder characterized by amyloid deposition in the walls of the blood vessels of the cerebrum, choroid plexus, cerebellum, spinal cord and retina. Plaques and neurofibrillary tangles are observed in the hippocampus. Clinical features include progressive ataxia, dementia, cataracts and deafness.SIMILARITY Belongs to the ITM2 family.SIMILARITY Contains 1 BRICHOS domain.") (DB_ID 57627) (description "recommendedName: Integral membrane protein 2B alternativeName: Protein E25B alternativeName: Transmembrane protein BRI component recommendedName: ABri/ADan amyloid peptide /component") (geneName "ITM2B" "BRI" "BRI2") (identifier "Q9Y287") (isSequenceChanged TRUE) (keyword "Amyloid" "Amyloidosis" "Cell membrane" "Cleavage on pair of basic residues" "Complete proteome" "Deafness" "Disease mutation" "Disulfide bond" "Glycoprotein" "Golgi apparatus" "Membrane" "Signal-anchor" "Transmembrane" "Transmembrane helix") (name "ITM2B") (referenceDatabase [GK_2]) (secondaryIdentifier "ITM2B_HUMAN" "Q9NYH1") (sequenceLength 266) (species [GK_48887])) ([GK_58841] of ReferenceGeneProduct (_displayName "[Hsa] UniProt:P61626 LYZ Lysozyme C alternativeName: 1,4-beta-N-acetylmuramidase C ") (checksum "1") (comment "FUNCTION Lysozymes have primarily a bacteriolytic function; those in tissues and body fluids are associated with the monocyte-macrophage system and enhance the activity of immunoagents.CATALYTIC ACTIVITY Hydrolysis of (1->4)-beta-linkages between N-acetylmuramic acid and N-acetyl-D-glucosamine residues in a peptidoglycan and between N-acetyl-D-glucosamine residues in chitodextrins.SUBUNIT Monomer.MISCELLANEOUS Lysozyme C is capable of both hydrolysis and transglycosylation; it shows also a slight esterase activity. It acts rapidly on both peptide-substituted and unsubstituted peptidoglycan, and slowly on chitin oligosaccharides.SIMILARITY Belongs to the glycosyl hydrolase 22 family.") (DB_ID 58841) (description " Lysozyme C alternativeName: 1,4-beta-N-acetylmuramidase C ") (geneName "LYZ" "LZM") (identifier "P61626") (isSequenceChanged TRUE) (keyword "3D-structure" "Amyloid" "Amyloidosis" "Antimicrobial" "Bacteriolytic enzyme" "Complete proteome" "Direct protein sequencing" "Disease mutation" "Disulfide bond" "Glycosidase" "Hydrolase" "Polymorphism" "Secreted" "Signal") (name "LYZ") (referenceDatabase [GK_2]) (secondaryIdentifier "LYSC_HUMAN" "P00695" "Q13170" "Q9UCF8") (sequenceLength 148) (species [GK_48887])) ([GK_59185] of ReferenceGeneProduct (_displayName "[Hsa] UniProt:Q08431 MFGE8 recommendedName: Lactadherin alternativeName: Breast epithelial antigen BA46 alternativeName: HMFG alternativeName: MFGM alternativeName: Milk fat globule-EGF factor 8 shortName:MFG-E8 alternativeName: Milk fat globule-EGF factor 8 shortName:MFG-E8 alternativeName: SED1 component recommendedName: Lactadherin short form /component component recommendedName: Medin /component") (checksum "1") (comment "TISSUE SPECIFICITY Mammary epithelial cell surfaces and aortic media. Overexpressed in several carcinomas.PTM Medin has a ragged N-terminus with minor species starting at Pro-264 and Gly-273.SIMILARITY Contains 1 EGF-like domain.SIMILARITY Contains 2 F5/8 type C domains.") (DB_ID 59185) (description "recommendedName: Lactadherin alternativeName: Breast epithelial antigen BA46 alternativeName: HMFG alternativeName: MFGM alternativeName: Milk fat globule-EGF factor 8 shortName:MFG-E8 alternativeName: Milk fat globule-EGF factor 8 shortName:MFG-E8 alternativeName: SED1 component recommendedName: Lactadherin short form /component component recommendedName: Medin /component") (geneName "MFGE8") (identifier "Q08431") (isSequenceChanged TRUE) (keyword "Alternative splicing" "Amyloid" "Angiogenesis" "Cell adhesion" "Complete proteome" "Direct protein sequencing" "Disulfide bond" "EGF-like domain" "Fertilization" "Glycoprotein" "Host-virus interaction" "Membrane" "Polymorphism" "Repeat" "Secreted" "Signal") (name "MFGE8") (referenceDatabase [GK_2]) (secondaryIdentifier "MFGM_HUMAN" "B2R6M7" "Q53FU9" "Q7Z3D2" "Q9BTL9") (sequenceLength 387) (species [GK_48887])) ([GK_6] of ReferenceDatabase (_displayName "COMPOUND") (accessUrl "http://www.genome.ad.jp/dbget-bin/www_bget?cpd:###ID###") (DB_ID 6) (name "COMPOUND") (url "http://www.genome.ad.jp/kegg/")) ([GK_611062] of PsiMod (_displayName "L-lysine residue [MOD:00021]") (DB_ID 611062) (definition "A protein modification that effectively converts a source amino acid residue to L-lysine.") (identifier "00021") (name "L-lysine residue") (referenceDatabase [GK_437354]) (synonym "(S)-2,6-diaminohexanoic acid" "Lys" "alpha,epsilon-diaminocaproic acid")) ([GK_611064] of PsiMod (_displayName "L-asparagine removal [MOD:01633]") (DB_ID 611064) (definition "A protein modification that effectively removes or replaces an L-asparagine.") (identifier "01633") (name "L-asparagine removal") (referenceDatabase [GK_437354])) ([GK_611065] of PsiMod (_displayName "L-lysine removal [MOD:01642]") (DB_ID 611065) (definition "A protein modification that effectively removes or replaces an L-lysine.") (identifier "01642") (name "L-lysine removal") (referenceDatabase [GK_437354])) ([GK_611066] of PsiMod (_displayName "L-arginine residue [MOD:00011]") (DB_ID 611066) (definition "A protein modification that effectively converts a source amino acid residue to an L-arginine.") (identifier "00011") (name "L-arginine residue") (referenceDatabase [GK_437354]) (synonym "(S)-2-amino-5-(carbamimidamido)pentanoic acid" "Arg")) ([GK_611067] of PsiMod (_displayName "L-glutamic acid residue [MOD:00015]") (DB_ID 611067) (definition "A protein modification that effectively converts a source amino acid residue to an L-glutamic acid.") (identifier "00015") (name "L-glutamic acid residue") (referenceDatabase [GK_437354]) (synonym "(S)-2-aminopentanedioic acid" "Glu")) ([GK_611068] of PsiMod (_displayName "glycine residue [MOD:00017]") (DB_ID 611068) (definition "A protein modification that effectively converts a source amino acid residue to a glycine.") (identifier "00017") (name "glycine residue") (referenceDatabase [GK_437354]) (synonym "aminoethanoic acid" "Gly")) ([GK_611069] of PsiMod (_displayName "L-proline residue [MOD:00024]") (DB_ID 611069) (definition "A protein modification that effectively converts a source amino acid residue to L-proline.") (identifier "00024") (name "L-proline residue") (referenceDatabase [GK_437354]) (synonym "(S)-2-pyrrolidinecarboxylic acid" "Pro" "pyrrolidine-2-carboxylic acid")) ([GK_611070] of PsiMod (_displayName "L-aspartic acid residue [MOD:00013]") (DB_ID 611070) (definition "A protein modification that effectively converts a source amino acid residue to an L-aspartic acid.") (identifier "00013") (name "L-aspartic acid residue") (referenceDatabase [GK_437354]) (synonym "(S)-2-aminobutanedioic acid" "Asp" "aminosuccinic acid")) ([GK_611072] of PsiMod (_displayName "L-proline removal [MOD:01645]") (DB_ID 611072) (definition "A protein modification that effectively removes or replaces an L-proline.") (identifier "01645") (name "L-proline removal") (referenceDatabase [GK_437354])) ([GK_611082] of PsiMod (_displayName "L-threonine residue [MOD:00026]") (DB_ID 611082) (definition "A protein modification that effectively converts a source amino acid residue to L-threonine.") (identifier "00026") (name "L-threonine residue") (referenceDatabase [GK_437354]) (synonym "(2S,3R)-2-amino-3-hydroxybutanoic acid" "Thr")) ([GK_611087] of PsiMod (_displayName "L-threonine removal [MOD:01647]") (DB_ID 611087) (definition "A protein modification that effectively removes or replaces an L-threonine.") (identifier "01647") (name "L-threonine removal") (referenceDatabase [GK_437354])) ([GK_611088] of PsiMod (_displayName "L-glutamine residue [MOD:00016]") (DB_ID 611088) (definition "A protein modification that effectively converts a source amino acid residue to an L-glutamine.") (identifier "00016") (name "L-glutamine residue") (referenceDatabase [GK_437354]) (synonym "(S)-2-amino-5-pentanediamic acid" "Gln")) ([GK_611093] of PsiMod (_displayName "L-leucine residue [MOD:00020]") (DB_ID 611093) (definition "A protein modification that effectively converts a source amino acid residue to an L-leucine.") (identifier "00020") (name "L-leucine residue") (referenceDatabase [GK_437354]) (synonym "(S)-2-amino-4-methylpentanoic acid" "Leu")) ([GK_61584] of ReferenceGeneProduct (_displayName "[Hsa] UniProt:P98160 HSPG2 recommendedName: Basement membrane-specific heparan sulfate proteoglycan core protein shortName:HSPG alternativeName: Perlecan shortName:PLC alternativeName: Perlecan shortName:PLC component recommendedName: Endorepellin /component component recommendedName: LG3 peptide /component") (checksum "1") (comment "TISSUE SPECIFICITY Found in the basement membranes.PTM Proteolytic processing produces the C-terminal angiogenic peptide, endorepellin. This peptide can be further processed to produce the LG3 peptide.MISCELLANEOUS The LG3 peptide has been found in the urine of patients with end-stage renal disease and in the amniotic fluid of pregnant women with premature rupture of fetal membranes.SIMILARITY Contains 4 EGF-like domains.SIMILARITY Contains 22 Ig-like C2-type (immunoglobulin-like) domains.SIMILARITY Contains 11 laminin EGF-like domains.SIMILARITY Contains 3 laminin G-like domains.SIMILARITY Contains 3 laminin IV type A domains.SIMILARITY Contains 4 LDL-receptor class A domains.SIMILARITY Contains 1 SEA domain.") (DB_ID 61584) (description "recommendedName: Basement membrane-specific heparan sulfate proteoglycan core protein shortName:HSPG alternativeName: Perlecan shortName:PLC alternativeName: Perlecan shortName:PLC component recommendedName: Endorepellin /component component recommendedName: LG3 peptide /component") (geneName "HSPG2") (identifier "P98160") (isSequenceChanged TRUE) (keyword "Angiogenesis" "Basement membrane" "Complete proteome" "Direct protein sequencing" "Disease mutation" "Disulfide bond" "EGF-like domain" "Extracellular matrix" "Glycoprotein" "Heparan sulfate" "Immunoglobulin domain" "Laminin EGF-like domain" "Polymorphism" "Proteoglycan" "Repeat" "Secreted" "Signal") (name "HSPG2") (referenceDatabase [GK_2]) (secondaryIdentifier "PGBM_HUMAN" "Q16287" "Q5SZI3" "Q9H3V5") (sequenceLength 4391) (species [GK_48887])) ([GK_62178] of ReferenceGeneProduct (_displayName "[Hsa] UniProt:P01236 PRL recommendedName: Prolactin shortName:PRL ") (checksum "1") (comment "FUNCTION Prolactin acts primarily on the mammary gland by promoting lactation.SIMILARITY Belongs to the somatotropin/prolactin family.") (DB_ID 62178) (description "recommendedName: Prolactin shortName:PRL ") (geneName "PRL") (identifier "P01236") (isSequenceChanged TRUE) (keyword "3D-structure" "Complete proteome" "Direct protein sequencing" "Disulfide bond" "Glycoprotein" "Hormone" "Lactation" "Secreted" "Signal") (name "PRL") (referenceDatabase [GK_2]) (secondaryIdentifier "PRL_HUMAN" "Q15199" "Q92996") (sequenceLength 227) (species [GK_48887])) ([GK_63118] of EntityWithAccessionedSequence (_displayName "[Hsa] RIP [cytosol]") (compartment [GK_70101]) (DB_ID 63118) (endCoordinate -1) (name "RIP" "Receptor-interacting serine/threonine protein kinase 2 (EC 2.7.1.-) (Serine/threonine protein kinase RIP) (Cell death protein RIP) (Receptor interacting protein)" "Receptor-interacting serine/threonine protein kinase 2 " "Serine/threonine protein kinase RIP" "Cell death protein RIP" "Receptor interacting protein") (referenceEntity [GK_63119]) (species [GK_48887]) (stableIdentifier [GK_367393]) (startCoordinate 1)) ([GK_63119] of ReferenceGeneProduct (_displayName "[Hsa] UniProt:Q13546 RIPK1 recommendedName: Receptor-interacting serine/threonine-protein kinase 1 ecNumber2.7.11.1/ecNumber alternativeName: Cell death protein RIP alternativeName: Receptor-interacting protein 1 shortName:RIP-1 alternativeName: Serine/threonine-protein kinase RIP ") (checksum "976E2428D525A9B2") (comment "FUNCTION Serine-threonine kinase which transduces inflammatory and cell-death signals (programmed necrosis) following death receptors ligation, activation of pathogen recognition receptors (PRRs), and DNA damage. Upon activation of TNFR1 by the TNF-alpha family cytokines, TRADD and TRAF2 are recruited to the receptor. Ubiquitination by TRAF2 via 'Lys-63'-link chains acts as a critical enhancer of communication with downstream signal transducers in the mitogen-activated protein kinase pathway and the NF-kappa-B pathway, which in turn mediate downstream events including the activation of genes encoding inflammatory molecules. Polyubiquitinated protein binds to IKBKG/NEMO, the regulatory subunit of the IKK complex, a critical event for NF-kappa-B activation. Interaction with other cellular RHIM-containing adapters initiates gene activation and cell death. RIPK1 and RIPK3 association, in particular, forms a necrosis-inducing complex.CATALYTIC ACTIVITY ATP + a protein = ADP + a phosphoprotein.ENZYME REGULATION Inhibited by necrostatin-1.SUBUNIT Interacts (via RIP homotypic interaction motif) with RIPK3 (via RIP homotypic interaction motif). Upon TNF-induced necrosis, the RIPK1-RIPK3 dimer further interacts with PGAM5 and MLKL; the formation of this complex leads to PGAM5 phosphorylation and increase in PGAM5 phosphatase activity. Interacts (via the death domain) with TNFRSF6 (via the death domain) and TRADD (via the death domain). Is recruited by TRADD to TNFRSF1A in a TNF-dependent process. Binds RNF216, EGFR, IKBKG, TRAF1, TRAF2 and TRAF3. Interacts with BNLF1. Interacts with SQSTM1 upon TNF-alpha stimulation. May interact with MAVS/IPS1. Interacts with ZFAND5. Interacts with RBCK1 (By similarity). Interacts with BIRC2/c-IAP1, BIRC3/c-IAP2 and XIAP/BIRC4. Upon TNF-induced necrosis, forms in complex with PGAM5, RIPK3 and MLKL.DOMAIN Contains a C-terminal death domain (DD) that engages other DD-containing proteins as well as a central (intermediate) region important for NF-kB activation and RHIM-dependent signaling.PTM Proteolytically cleaved by caspase-8 during TNF-induced apoptosis. Cleavage abolishes NF-kappa-B activation and enhances pro-apoptotic signaling through the TRADD-FADD interaction.PTM RIPK1 and RIPK3 undergo reciprocal auto- and trans-phosphorylation. Phosphorylation of Ser-161 by RIPK3 is necessary for the formation of the necroptosis-inducing complex.PTM Ubiquitinated by 'Lys-11'-, 'Lys-48'-, 'Lys-63'- and linear-linked type ubiquitin. Polyubiquitination with 'Lys-63'-linked chains by TRAF2 induces association with the IKK complex. Deubiquitination of 'Lys-63'-linked chains and polyubiquitination with 'Lys-48'-linked chains by TNFAIP3 leads to RIPK1 proteasomal degradation and consequently down-regulates TNF-alpha-induced NFkappa-B signaling. Linear polyubiquitinated; the head-to-tail polyubiquitination is mediated by the LUBAC complex. LPS-mediated activation of NF-kappa-B. Also ubiquitinated with 'Lys-11'-linked chains. Polyubiquitinated with 'Lys-48' and 'Lys-63'-linked chains by BIRC2/c-IAP1 and BIRC3/c-IAP2, leading to activation of NF-kappa-B.SIMILARITY Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family.SIMILARITY Contains 1 death domain.SIMILARITY Contains 1 protein kinase domain.") (DB_ID 63119) (description "recommendedName: Receptor-interacting serine/threonine-protein kinase 1 ecNumber2.7.11.1/ecNumber alternativeName: Cell death protein RIP alternativeName: Receptor-interacting protein 1 shortName:RIP-1 alternativeName: Serine/threonine-protein kinase RIP ") (geneName "RIPK1" "RIP" "RIP1") (identifier "Q13546") (isSequenceChanged FALSE) (keyword "Alternative splicing" "ATP-binding" "Cell membrane" "Complete proteome" "Cytoplasm" "Isopeptide bond" "Kinase" "Membrane" "Necrosis" "Nucleotide-binding" "Phosphoprotein" "Polymorphism" "Reference proteome" "Serine/threonine-protein kinase" "Transferase" "Ubl conjugation") (name "RIPK1") (referenceDatabase [GK_2]) (secondaryIdentifier "RIPK1_HUMAN" "A0AV89" "B2RAG1" "B4E3F9" "Q13180" "Q59H33") (sequenceLength 671) (species [GK_48887])) ([GK_64108] of ReferenceGeneProduct (_displayName "[Hsa] UniProt:P02735 SAA1 recommendedName: Serum amyloid A protein shortName:SAA component recommendedName: Amyloid protein A alternativeName: Amyloid fibril protein AA /component component recommendedName: Serum amyloid protein A(2-104) /component component recommendedName: Serum amyloid protein A(3-104) /component component recommendedName: Serum amyloid protein A(2-103) /component component recommendedName: Serum amyloid protein A(2-102) /component component recommendedName: Serum amyloid protein A(4-101) /component") (checksum "1") (comment "FUNCTION Major acute phase reactant. Apolipoprotein of the HDL complex.INDUCTION Upon cytokine stimulation.PTM This protein is the precursor of amyloid protein A, which is formed by the removal of approximately 24 residues from the C-terminal end.POLYMORPHISM Both SAA1 and SAA2 have a number of alleles. We use here the nomenclature of PubMed:1546977. The sequence shown is that of 1-alpha.DISEASE Note=Reactive, secondary amyloidosis is characterized by the extracellular accumulation in various tissues of the SAA protein. These deposits are highly insoluble and resistant to proteolysis; they disrupt tissue structure and compromise function.DISEASE Note=Elevated serum SSA protein levels may be associated with lung cancer.SIMILARITY Belongs to the SAA family.") (DB_ID 64108) (description "recommendedName: Serum amyloid A protein shortName:SAA component recommendedName: Amyloid protein A alternativeName: Amyloid fibril protein AA /component component recommendedName: Serum amyloid protein A(2-104) /component component recommendedName: Serum amyloid protein A(3-104) /component component recommendedName: Serum amyloid protein A(2-103) /component component recommendedName: Serum amyloid protein A(2-102) /component component recommendedName: Serum amyloid protein A(4-101) /component") (geneName "SAA1" "" "" "SAA2") (identifier "P02735") (isSequenceChanged TRUE) (keyword "Acute phase" "Amyloid" "Amyloidosis" "Complete proteome" "Direct protein sequencing" "HDL" "Methylation" "Polymorphism" "Secreted" "Signal") (name "SAA1") (referenceDatabase [GK_2]) (secondaryIdentifier "SAA_HUMAN" "P02736" "P02737" "Q16730" "Q16834" "Q16835" "Q16879" "Q3KRB3" "Q6FG67" "Q96QN0" "Q9UCK9" "Q9UCL0") (sequenceLength 122) (species [GK_48887])) ([GK_64128] of ReferenceGeneProduct (_displayName "[Hsa] UniProt:P02743 APCS recommendedName: Serum amyloid P-component shortName:SAP alternativeName: 9.5S alpha-1-glycoprotein component recommendedName: Serum amyloid P-component(1-203) /component") (checksum "1") (comment "FUNCTION Can interact with DNA and histones and may scavenge nuclear material released from damaged circulating cells. May also function as a calcium-dependent lectin.COFACTOR Binds 2 calcium ions per subunit.SUBUNIT Homopentamer. Pentaxin (or pentraxin) have a discoid arrangement of 5 non-covalently bound subunits.DISEASE Note=SAP is a precursor of amyloid component P which is found in basement membrane and associated with amyloid deposits.SIMILARITY Belongs to the pentaxin family.SIMILARITY Contains 1 pentaxin domain.") (DB_ID 64128) (description "recommendedName: Serum amyloid P-component shortName:SAP alternativeName: 9.5S alpha-1-glycoprotein component recommendedName: Serum amyloid P-component(1-203) /component") (geneName "APCS" "PTX2") (identifier "P02743") (isSequenceChanged TRUE) (keyword "3D-structure" "Acetylation" "Amyloid" "Calcium" "Complete proteome" "Direct protein sequencing" "Disulfide bond" "Glycoprotein" "Lectin" "Metal-binding" "Phosphoprotein" "Polymorphism" "Secreted" "Signal") (name "APCS") (referenceDatabase [GK_2]) (secondaryIdentifier "SAMP_HUMAN") (sequenceLength 223) (species [GK_48887])) ([GK_64296] of ReferenceGeneProduct (_displayName "[Hsa] UniProt:P04279 SEMG1 recommendedName: Semenogelin-1 alternativeName: Semenogelin I shortName:SGI alternativeName: Semenogelin I shortName:SGI component recommendedName: Alpha-inhibin-92 /component component recommendedName: Alpha-inhibin-31 /component component recommendedName: Seminal basic protein /component") (checksum "1") (comment "FUNCTION Predominant protein in semen. It participates in the formation of a gel matrix entrapping the accessory gland secretions and ejaculated spermatozoa. Fragments of semenogelin and/or fragments of the related proteins may contribute to the activation of progressive sperm movements as the gel-forming proteins are fragmented by KLK3/PSA.FUNCTION Alpha-inhibin-92 and alpha-inhibin-31, derived from the proteolytic degradation of semenogelin, inhibit the secretion of pituitary follicle-stimulating hormone.SUBUNIT Occurs in disulfide-linked complexes which may also contain two less abundant 71- and 76-kDa semenogelin-related polypeptides.TISSUE SPECIFICITY Seminal vesicle.PTM Transglutaminase substrate.PTM Rapidly cleaved after ejaculation by KLK3/PSA, resulting in liquefaction of the semen coagulum and the progressive release of motile spermatozoa.SIMILARITY Belongs to the semenogelin family.") (DB_ID 64296) (description "recommendedName: Semenogelin-1 alternativeName: Semenogelin I shortName:SGI alternativeName: Semenogelin I shortName:SGI component recommendedName: Alpha-inhibin-92 /component component recommendedName: Alpha-inhibin-31 /component component recommendedName: Seminal basic protein /component") (geneName "SEMG1" "SEMG") (identifier "P04279") (isSequenceChanged TRUE) (keyword "Alternative splicing" "Complete proteome" "Direct protein sequencing" "Disulfide bond" "Polymorphism" "Pyrrolidone carboxylic acid" "Repeat" "Secreted" "Signal") (name "SEMG1") (referenceDatabase [GK_2]) (secondaryIdentifier "SEMG1_HUMAN" "Q53ZV0" "Q53ZV1" "Q53ZV2" "Q6X4I9" "Q6Y809" "Q6Y822" "Q6Y823" "Q86U64" "Q96QM3") (sequenceLength 462) (species [GK_48887])) ([GK_6486] of GO_CellularComponent (_displayName "host") (accession "0018995") (DB_ID 6486) (definition "Any organism in which another organism, especially a parasite or symbiont, spends part or all of its life cycle and from which it obtains nourishment and/or protection.") (instanceOf [GK_447576]) (name "host") (referenceDatabase [GK_1])) ([GK_6542] of GO_BiologicalProcess (_displayName "induction of apoptosis") (accession "0006917") (DB_ID 6542) (definition "A process that directly activates any of the steps required for cell death by apoptosis.") (instanceOf [GK_6543] [GK_160565]) (name "induction of apoptosis") (referenceDatabase [GK_1])) ([GK_6543] of GO_BiologicalProcess (_displayName "induction of programmed cell death") (accession "0012502") (DB_ID 6543) (definition "A process which directly activates any of the steps required for programmed cell death.") (instanceOf [GK_160227]) (name "induction of programmed cell death") (referenceDatabase [GK_1])) ([GK_65462] of ReferenceGeneProduct (_displayName "[Hsa] UniProt:P37840 SNCA recommendedName: Alpha-synuclein alternativeName: Non-A beta component of AD amyloid alternativeName: Non-A4 component of amyloid precursor shortName:NACP alternativeName: Non-A4 component of amyloid precursor shortName:NACP ") (checksum "1") (comment "FUNCTION May be involved in the regulation of dopamine release and transport. Induces fibrillization of microtubule-associated protein tau. Reduces neuronal responsiveness to various apoptotic stimuli, leading to a decreased caspase-3 activation.TISSUE SPECIFICITY Expressed principally in brain but is also expressed in low concentrations in all tissues examined except in liver. Concentrated in presynaptic nerve terminals.PTM Hallmark lesions of neurodegenerative synucleinopathies contain alpha-synuclein that is modified by nitration of tyrosine residues and possibly by dityrosine cross-linking to generated stable oligomers.DISEASE Note=Genetic alterations of SNCA resulting in aberrant polymerization into fibrils, are associated with several neurodegenerative diseases (synucleinopathies). SNCA fibrillar aggregates represent the major non A-beta component of Alzheimer disease amyloid plaque, and a major component of Lewy body inclusions. They are also found within Lewy body (LB)-like intraneuronal inclusions, glial inclusions and axonal spheroids in neurodegeneration with brain iron accumulation type 1.DISEASE Defects in SNCA are the cause of Parkinson disease type 4 (PARK4) [MIM:605543]. A complex neurodegenerative disorder with manifestations ranging from typical Parkinson disease to dementia with Lewy bodies. Clinical features include parkinsonian symptoms (tremor, rigidity, postural instability and bradykinesia), dementia, diffuse Lewy body pathology, autonomic dysfunction, hallucinations and paranoia.DISEASE Defects in SNCA are the cause of dementia Lewy body (DLB) [MIM:127750]. A neurodegenerative disorder clinically characterized by mental impairment leading to dementia, parkinsonism, often with fluctuating cognitive function, visual hallucinations, falls, syncopal episodes, and sensitivity to neuroleptic medication. Brainstem or cortical intraneuronal accumulations of aggregated proteins (Lewy bodies) are the only essential pathologic features. Patients may also have hippocampal and neocortical senile plaques, sometimes in sufficient number to fulfill the diagnostic criteria for Alzheimer disease.SIMILARITY Belongs to the synuclein family.") (DB_ID 65462) (description "recommendedName: Alpha-synuclein alternativeName: Non-A beta component of AD amyloid alternativeName: Non-A4 component of amyloid precursor shortName:NACP alternativeName: Non-A4 component of amyloid precursor shortName:NACP ") (geneName "SNCA" "NACP" "PARK1") (identifier "P37840") (isSequenceChanged TRUE) (keyword "3D-structure" "Alternative splicing" "Alzheimer disease" "Amyloid" "Cell junction" "Complete proteome" "Cytoplasm" "Direct protein sequencing" "Disease mutation" "Membrane" "Neurodegeneration" "Nucleus" "Parkinson disease" "Parkinsonism" "Phosphoprotein" "Repeat" "Synapse" "Ubl conjugation") (name "SNCA") (referenceDatabase [GK_2]) (secondaryIdentifier "SYUA_HUMAN" "A8K2A4" "Q13701" "Q4JHI3" "Q6IAU6") (sequenceLength 140) (species [GK_48887])) ([GK_65505] of EntityWithAccessionedSequence (_displayName "[Hsa] TRAIL receptor-2 [plasma membrane]") (compartment [GK_876]) (DB_ID 65505) (endCoordinate 440) (name "TRAIL receptor-2" "Tumor necrosis factor receptor superfamily member 10B precursor (Death receptor 5) (TNF-related apoptosis-inducing ligand receptor 2) (TRAIL receptor-2) (TRAIL-R2)" "Tumor necrosis factor receptor superfamily member 10B precursor" "Death receptor 5" "TNF-related apoptosis-inducing ligand receptor 2" "TRAIL-R2") (referenceEntity [GK_65506]) (species [GK_48887]) (stableIdentifier [GK_371450]) (startCoordinate 56)) ([GK_65506] of ReferenceGeneProduct (_displayName "[Hsa] UniProt:O14763 TNFRSF10B recommendedName: Tumor necrosis factor receptor superfamily member 10B alternativeName: Death receptor 5 alternativeName: TNF-related apoptosis-inducing ligand receptor 2 shortName:TRAIL receptor 2 shortName:TRAIL-R2 cdAntigenNameCD262/cdAntigenName") (checksum "60358EAF2A835870") (comment "FUNCTION Receptor for the cytotoxic ligand TNFSF10/TRAIL. The adapter molecule FADD recruits caspase-8 to the activated receptor. The resulting death-inducing signaling complex (DISC) performs caspase-8 proteolytic activation which initiates the subsequent cascade of caspases (aspartate-specific cysteine proteases) mediating apoptosis. Promotes the activation of NF-kappa-B. Essential for ER stress-induced apoptosis.SUBUNIT Homotrimer. Can interact with TRADD and RIPK1.TISSUE SPECIFICITY Widely expressed in adult and fetal tissues; very highly expressed in tumor cell lines such as HeLaS3, K-562, HL-60, SW480, A-549 and G-361; highly expressed in heart, peripheral blood lymphocytes, liver, pancreas, spleen, thymus, prostate, ovary, uterus, placenta, testis, esophagus, stomach and throughout the intestinal tract; not detectable in brain.INDUCTION By ER stress. Regulated by p53/TP53.DISEASE Defects in TNFRSF10B may be a cause of head and neck squamous cell carcinomas (HNSCC) [MIM:275355]; also known as squamous cell carcinoma of the head and neck.SIMILARITY Contains 1 death domain.SIMILARITY Contains 3 TNFR-Cys repeats.") (DB_ID 65506) (description "recommendedName: Tumor necrosis factor receptor superfamily member 10B alternativeName: Death receptor 5 alternativeName: TNF-related apoptosis-inducing ligand receptor 2 shortName:TRAIL receptor 2 shortName:TRAIL-R2 cdAntigenNameCD262/cdAntigenName") (geneName "TNFRSF10B" "DR5" "KILLER" "TRAILR2" "TRICK2" "ZTNFR9" "UNQ160/PRO186") (identifier "O14763") (isSequenceChanged FALSE) (keyword "3D-structure" "Alternative splicing" "Apoptosis" "Complete proteome" "Direct protein sequencing" "Disulfide bond" "Membrane" "Polymorphism" "Receptor" "Reference proteome" "Repeat" "Signal" "Transmembrane" "Transmembrane helix") (name "TNFRSF10B") (referenceDatabase [GK_2]) (secondaryIdentifier "TR10B_HUMAN" "O14720" "O15508" "O15517" "O15531" "Q6UXM8" "Q7Z360" "Q9BVE0") (sequenceLength 440) (species [GK_48887])) ([GK_66186] of EntityWithAccessionedSequence (_displayName "[Hsa] TRAIL [extracellular region]") (compartment [GK_984]) (DB_ID 66186) (endCoordinate 281) (name "TRAIL" "Tumor necrosis factor ligand superfamily member 10 (TNF-related apoptosis inducing ligand) (TRAIL protein) (Apo-2 ligand) (Apo-2L)" "Tumor necrosis factor ligand superfamily member 10" "TNF-related apoptosis inducing ligand" "TRAIL protein" "Apo-2 ligand" "Apo-2L") (referenceEntity [GK_66187]) (species [GK_48887]) (stableIdentifier [GK_366902]) (startCoordinate 1)) ([GK_66187] of ReferenceGeneProduct (_displayName "[Hsa] UniProt:P50591 TNFSF10 recommendedName: Tumor necrosis factor ligand superfamily member 10 alternativeName: Apo-2 ligand shortName:Apo-2L alternativeName: TNF-related apoptosis-inducing ligand shortName:Protein TRAIL cdAntigenNameCD253/cdAntigenName") (checksum "DDAAAF78DAAB2F6D") (comment "FUNCTION Cytokine that binds to TNFRSF10A/TRAILR1, TNFRSF10B/TRAILR2, TNFRSF10C/TRAILR3, TNFRSF10D/TRAILR4 and possibly also to TNFRSF11B/OPG. Induces apoptosis. Its activity may be modulated by binding to the decoy receptors TNFRSF10C/TRAILR3, TNFRSF10D/TRAILR4 and TNFRSF11B/OPG that cannot induce apoptosis.COFACTOR Binds 1 zinc ion per trimer.SUBUNIT Homotrimer.TISSUE SPECIFICITY Widespread; most predominant in spleen, lung and prostate.SIMILARITY Belongs to the tumor necrosis factor family.") (DB_ID 66187) (description "recommendedName: Tumor necrosis factor ligand superfamily member 10 alternativeName: Apo-2 ligand shortName:Apo-2L alternativeName: TNF-related apoptosis-inducing ligand shortName:Protein TRAIL cdAntigenNameCD253/cdAntigenName") (geneName "TNFSF10" "APO2L" "TRAIL") (identifier "P50591") (isSequenceChanged TRUE) (keyword "3D-structure" "Alternative splicing" "Apoptosis" "Complete proteome" "Cytokine" "Membrane" "Metal-binding" "Polymorphism" "Reference proteome" "Signal-anchor" "Transmembrane" "Transmembrane helix" "Zinc") (name "TNFSF10") (referenceDatabase [GK_2]) (secondaryIdentifier "TNF10_HUMAN" "A1Y9B3") (sequenceLength 281) (species [GK_48887])) ([GK_66212] of EntityWithAccessionedSequence (_displayName "[Hsa] FASL [extracellular region]") (compartment [GK_984]) (DB_ID 66212) (endCoordinate 281) (name "FASL" "Tumor necrosis factor ligand superfamily member 6 (FAS antigen ligand) (Apoptosis antigen ligand) (APTL) (CD178 antigen)" "Tumor necrosis factor ligand superfamily member 6" "FAS antigen ligand" "Apoptosis antigen ligand" "APTL" "CD178 antigen") (referenceEntity [GK_66213]) (species [GK_48887]) (stableIdentifier [GK_364838]) (startCoordinate 1)) ([GK_66213] of ReferenceGeneProduct (_displayName "[Hsa] UniProt:P48023 FASLG recommendedName: Tumor necrosis factor ligand superfamily member 6 alternativeName: Apoptosis antigen ligand shortName:APTL alternativeName: CD95 ligand shortName:CD95-L alternativeName: Fas antigen ligand shortName:Fas ligand shortName:FasL cdAntigenNameCD178/cdAntigenName component recommendedName: Tumor necrosis factor ligand superfamily member 6, membrane form /component component recommendedName: Tumor necrosis factor ligand superfamily member 6, soluble form alternativeName: Receptor-binding FasL ectodomain alternativeName: Soluble Fas ligand shortName:sFasL /component component recommendedName: ADAM10-processed FasL form shortName:APL /component component recommendedName: FasL intracellular domain shortName:FasL ICD alternativeName: SPPL2A-processed FasL form shortName:SPA /component") (checksum "A8A6EB358246E9BB") (comment "FUNCTION Cytokine that binds to TNFRSF6/FAS, a receptor that transduces the apoptotic signal into cells. May be involved in cytotoxic T-cell mediated apoptosis and in T-cell development. TNFRSF6/FAS-mediated apoptosis may have a role in the induction of peripheral tolerance, in the antigen-stimulated suicide of mature T-cells, or both. Binding to the decoy receptor TNFRSF6B/DcR3 modulates its effects.FUNCTION The FasL intracellular domain (FasL ICD) cytoplasmic form induces gene transcription inhibition.SUBUNIT Homotrimer (Probable). Interacts with ARHGAP9, BAIAP2L1, BTK, CACNB3, CACNB4, CRK, DLG2, DNMBP, DOCK4, EPS8L3, FGR, FYB, FYN, HCK, ITK, ITSN2, KALRN, LYN, MACC1, MIA, MPP4, MYO15A, NCF1, NCK1, NCK2, NCKIPSD, OSTF1, PIK3R1, PSTPIP1, RIMBP3C, SAMSN1, SH3GL3, SH3PXD2B, SH3PXD2A, SH3RF2, SKAP2, SNX33, SNX9, SORBS3, SPTA1, SRC, SRGAP1, SRGAP2, SRGAP3, TEC, TJP3 and YES1.PTM The soluble form derives from the membrane form by proteolytic processing. The membrane-bound form undergoes two successive intramembrane proteolytic cleavages. The first one is processed by ADAM10 producing an N-terminal fragment, which lacks the receptor-binding extracellular domain. This ADAM10-processed FasL (FasL APL) remnant form is still membrane anchored and further processed by SPPL2A that liberates the FasL intracellular domain (FasL ICD). FasL shedding by ADAM10 is a prerequisite for subsequent intramembrane cleavage by SPPL2A in T-cells.PTM N-glycosylated.PTM Phosphorylated by FGR on tyrosine residues; this is required for ubiquitination and subsequent internalization.PTM Monoubiquitinated.DISEASE Defects in FASLG are the cause of autoimmune lymphoproliferative syndrome type 1B (ALPS1B) [MIM:601859]; also known as Canale-Smith syndrome (CSS). ALPS is a childhood syndrome involving hemolytic anemia and thrombocytopenia with massive lymphadenopathy and splenomegaly.SIMILARITY Belongs to the tumor necrosis factor family.") (DB_ID 66213) (description "recommendedName: Tumor necrosis factor ligand superfamily member 6 alternativeName: Apoptosis antigen ligand shortName:APTL alternativeName: CD95 ligand shortName:CD95-L alternativeName: Fas antigen ligand shortName:Fas ligand shortName:FasL cdAntigenNameCD178/cdAntigenName component recommendedName: Tumor necrosis factor ligand superfamily member 6, membrane form /component component recommendedName: Tumor necrosis factor ligand superfamily member 6, soluble form alternativeName: Receptor-binding FasL ectodomain alternativeName: Soluble Fas ligand shortName:sFasL /component component recommendedName: ADAM10-processed FasL form shortName:APL /component component recommendedName: FasL intracellular domain shortName:FasL ICD alternativeName: SPPL2A-processed FasL form shortName:SPA /component") (geneName "FASLG" "APT1LG1" "CD95L" "FASL" "TNFSF6") (identifier "P48023") (isSequenceChanged TRUE) (keyword "3D-structure" "Alternative splicing" "Apoptosis" "Cell membrane" "Complete proteome" "Cytokine" "Cytoplasmic vesicle" "Disulfide bond" "Glycoprotein" "Lysosome" "Membrane" "Nucleus" "Polymorphism" "Reference proteome" "Repressor" "Secreted" "Signal-anchor" "Transcription" "Transcription regulation" "Transmembrane" "Transmembrane helix" "Ubl conjugation") (name "FASLG") (referenceDatabase [GK_2]) (secondaryIdentifier "TNFL6_HUMAN" "Q9BZP9") (sequenceLength 281) (species [GK_48887])) ([GK_66220] of EntityWithAccessionedSequence (_displayName "[Hsa] TNF-alpha [plasma membrane]") (compartment [GK_876]) (DB_ID 66220) (endCoordinate 233) (name "TNF-alpha" "Tumor necrosis factor precursor (TNF-alpha) (Tumor necrosis factor ligand superfamily member 2) (Cachectin)" "Tumor necrosis factor precursor" "Tumor necrosis factor ligand superfamily member 2" "TNF-a" "Cachectin") (referenceEntity [GK_66221]) (species [GK_48887]) (stableIdentifier [GK_370748]) (startCoordinate 1)) ([GK_66221] of ReferenceGeneProduct (_displayName "[Hsa] UniProt:P01375 TNF recommendedName: Tumor necrosis factor alternativeName: Cachectin alternativeName: TNF-alpha alternativeName: Tumor necrosis factor ligand superfamily member 2 shortName:TNF-a component recommendedName: Tumor necrosis factor, membrane form alternativeName: N-terminal fragment shortName:NTF /component component recommendedName: Intracellular domain 1 shortName:ICD1 /component component recommendedName: Intracellular domain 2 shortName:ICD2 /component component recommendedName: C-domain 1 /component component recommendedName: C-domain 2 /component component recommendedName: Tumor necrosis factor, soluble form /component") (checksum "3DF90F96C9031FFE") (comment "FUNCTION Cytokine that binds to TNFRSF1A/TNFR1 and TNFRSF1B/TNFBR. It is mainly secreted by macrophages and can induce cell death of certain tumor cell lines. It is potent pyrogen causing fever by direct action or by stimulation of interleukin-1 secretion and is implicated in the induction of cachexia, Under certain conditions it can stimulate cell proliferation and induce cell differentiation.FUNCTION The TNF intracellular domain (ICD) form induces IL12 production in dendritic cells.SUBUNIT Homotrimer. Interacts with SPPL2B.PTM The soluble form derives from the membrane form by proteolytic processing. The membrane-bound form is further proteolytically processed by SPPL2A or SPPL2B through regulated intramembrane proteolysis producing TNF intracellular domains (ICD1 and ICD2) released in the cytosol and TNF C-domain 1 and C-domain 2 secreted into the extracellular space.PTM The membrane form, but not the soluble form, is phosphorylated on serine residues. Dephosphorylation of the membrane form occurs by binding to soluble TNFRSF1A/TNFR1.PTM O-glycosylated; glycans contain galactose, N-acetylgalactosamine and N-acetylneuraminic acid.POLYMORPHISM Genetic variations in TNF influence susceptibility to hepatitis B virus (HBV) infection [MIM:610424].POLYMORPHISM Genetic variations in TNF are involved in susceptibility to malaria [MIM:611162].DISEASE Genetic variations in TNF are a cause of susceptibility psoriatic arthritis (PSORAS) [MIM:607507]. PSORAS is an inflammatory, seronegative arthritis associated with psoriasis. It is a heterogeneous disorder ranging from a mild, non-destructive disease to a severe, progressive, erosive arthropathy. Five types of psoriatic arthritis have been defined: asymmetrical oligoarthritis characterized by primary involvement of the small joints of the fingers or toes; asymmetrical arthritis which involves the joints of the extremities; symmetrical polyarthritis characterized by a rheumatoidlike pattern that can involve hands, wrists, ankles, and feet; arthritis mutilans, which is a rare but deforming and destructive condition; arthritis of the sacroiliac joints and spine (psoriatic spondylitis).SIMILARITY Belongs to the tumor necrosis factor family.") (DB_ID 66221) (description "recommendedName: Tumor necrosis factor alternativeName: Cachectin alternativeName: TNF-alpha alternativeName: Tumor necrosis factor ligand superfamily member 2 shortName:TNF-a component recommendedName: Tumor necrosis factor, membrane form alternativeName: N-terminal fragment shortName:NTF /component component recommendedName: Intracellular domain 1 shortName:ICD1 /component component recommendedName: Intracellular domain 2 shortName:ICD2 /component component recommendedName: C-domain 1 /component component recommendedName: C-domain 2 /component component recommendedName: Tumor necrosis factor, soluble form /component") (geneName "TNF" "TNFA" "TNFSF2") (identifier "P01375") (isSequenceChanged TRUE) (keyword "3D-structure" "Cell membrane" "Complete proteome" "Cytokine" "Direct protein sequencing" "Disulfide bond" "Glycoprotein" "Lipoprotein" "Membrane" "Myristate" "Phosphoprotein" "Polymorphism" "Reference proteome" "Secreted" "Signal-anchor" "Transmembrane" "Transmembrane helix") (name "TNF") (referenceDatabase [GK_2]) (secondaryIdentifier "TNFA_HUMAN" "O43647" "Q9P1Q2" "Q9UIV3") (sequenceLength 233) (species [GK_48887])) ([GK_66248] of EntityWithAccessionedSequence (_displayName "[Hsa] FAS Receptor [plasma membrane]") (compartment [GK_876]) (DB_ID 66248) (endCoordinate 335) (name "FAS Receptor" "Tumor necrosis factor receptor superfamily member 6 precursor (FASL receptor) (Apoptosis-mediating surface antigen FAS) (Apo-1 antigen) (CD95)" "Tumor necrosis factor receptor superfamily member 6 precursor" "FASL receptor" "Apoptosis-mediating surface antigen FAS" "Apo-1 antigen" "CD95") (referenceEntity [GK_66249]) (species [GK_48887]) (stableIdentifier [GK_364006]) (startCoordinate 26)) ([GK_66249] of ReferenceGeneProduct (_displayName "[Hsa] UniProt:P25445 FAS recommendedName: Tumor necrosis factor receptor superfamily member 6 alternativeName: Apo-1 antigen alternativeName: Apoptosis-mediating surface antigen FAS alternativeName: FASLG receptor cdAntigenNameCD95/cdAntigenName") (checksum "0139942535111410") (comment "FUNCTION Receptor for TNFSF6/FASLG. The adapter molecule FADD recruits caspase-8 to the activated receptor. The resulting death-inducing signaling complex (DISC) performs caspase-8 proteolytic activation which initiates the subsequent cascade of caspases (aspartate-specific cysteine proteases) mediating apoptosis. FAS-mediated apoptosis may have a role in the induction of peripheral tolerance, in the antigen-stimulated suicide of mature T-cells, or both. The secreted isoforms 2 to 6 block apoptosis (in vitro).SUBUNIT Binds DAXX. Interacts with HIPK3. Part of a complex containing HIPK3 and FADD (By similarity). Binds RIPK1 and FAIM2. Interacts with BRE and FEM1B. Interacts with FADD.TISSUE SPECIFICITY Isoform 1 and isoform 6 are expressed at equal levels in resting peripheral blood mononuclear cells. After activation there is an increase in isoform 1 and decrease in the levels of isoform 6.DOMAIN Contains a death domain involved in the binding of FADD, and maybe to other cytosolic adapter proteins.PTM N- and O-glycosylated. O-glycosylated with core 1 or possibly core 8 glycans.DISEASE Defects in FAS are the cause of autoimmune lymphoproliferative syndrome type 1A (ALPS1A) [MIM:601859]; also known as Canale-Smith syndrome (CSS). ALPS is a childhood syndrome involving hemolytic anemia and thrombocytopenia with massive lymphadenopathy and splenomegaly.SIMILARITY Contains 1 death domain.SIMILARITY Contains 3 TNFR-Cys repeats.") (DB_ID 66249) (description "recommendedName: Tumor necrosis factor receptor superfamily member 6 alternativeName: Apo-1 antigen alternativeName: Apoptosis-mediating surface antigen FAS alternativeName: FASLG receptor cdAntigenNameCD95/cdAntigenName") (geneName "FAS" "APT1" "FAS1" "TNFRSF6") (identifier "P25445") (isSequenceChanged FALSE) (keyword "3D-structure" "Alternative splicing" "Apoptosis" "Cell membrane" "Complete proteome" "Direct protein sequencing" "Disease mutation" "Disulfide bond" "Glycoprotein" "Membrane" "Phosphoprotein" "Polymorphism" "Receptor" "Reference proteome" "Repeat" "Secreted" "Signal" "Transmembrane" "Transmembrane helix") (name "FAS") (referenceDatabase [GK_2]) (secondaryIdentifier "TNR6_HUMAN" "A9UJX4" "B6VNV4" "Q14292" "Q14293" "Q14294" "Q14295" "Q16652" "Q5T9P1" "Q5T9P2" "Q5T9P3" "Q6SSE9") (sequenceLength 335) (species [GK_48887])) ([GK_66344] of EntityWithAccessionedSequence (_displayName "[Hsa] TNF-RI [plasma membrane]") (compartment [GK_876]) (DB_ID 66344) (endCoordinate 455) (name "TNF-RI" "Tumor necrosis factor receptor superfamily member 1A precursor (p60) (TNF-R1) (TNF-RI) (p55) (CD120a) (Contains: Tumor necrosis factor binding protein 1 (TBPI))" "Tumor necrosis factor receptor superfamily member 1A precursor" "p60" "TNF-R1" "p55" "CD120a" "Tumor necrosis factor binding protein 1" "TBPI") (referenceEntity [GK_66345]) (species [GK_48887]) (stableIdentifier [GK_368490]) (startCoordinate 22)) ([GK_66345] of ReferenceGeneProduct (_displayName "[Hsa] UniProt:P19438 TNFRSF1A recommendedName: Tumor necrosis factor receptor superfamily member 1A alternativeName: Tumor necrosis factor receptor 1 shortName:TNF-R1 alternativeName: Tumor necrosis factor receptor type I shortName:TNF-RI shortName:TNFR-I alternativeName: p55 alternativeName: p60 cdAntigenNameCD120a/cdAntigenName component recommendedName: Tumor necrosis factor receptor superfamily member 1A, membrane form /component component recommendedName: Tumor necrosis factor-binding protein 1 shortName:TBPI /component") (checksum "4CEFBA96D03B8225") (comment "FUNCTION Receptor for TNFSF2/TNF-alpha and homotrimeric TNFSF1/lymphotoxin-alpha. The adapter molecule FADD recruits caspase-8 to the activated receptor. The resulting death-inducing signaling complex (DISC) performs caspase-8 proteolytic activation which initiates the subsequent cascade of caspases (aspartate-specific cysteine proteases) mediating apoptosis. Contributes to the induction of non-cytocidal TNF effects including anti-viral state and activation of the acid sphingomyelinase.SUBUNIT Binding of TNF to the extracellular domain leads to homotrimerization. The aggregated death domains provide a novel molecular interface that interacts specifically with the death domain of TRADD. Various TRADD-interacting proteins such as TRAFS, RIPK1 and possibly FADD, are recruited to the complex by their association with TRADD. This complex activates at least two distinct signaling cascades, apoptosis and NF-kappa-B signaling. Interacts with BAG4, BRE, FEM1B, GRB2, SQSTM1 and TRPC4AP. Interacts with HCV core protein. Interacts with human cytomegalovirus/HHV-5 protein UL138.DOMAIN The domain that induces A-SMASE is probably identical to the death domain. The N-SMASE activation domain (NSD) is both necessary and sufficient for activation of N-SMASE.PTM The soluble form is produced from the membrane form by proteolytic processing.DISEASE Defects in TNFRSF1A are the cause of familial hibernian fever (FHF) [MIM:142680]; also known as tumor necrosis factor receptor-associated periodic syndrome (TRAPS). FHF is a hereditary periodic fever syndrome characterized by recurrent fever, abdominal pain, localized tender skin lesions and myalgia. Reactive amyloidosis is the main complication and occurs in 25% of cases.DISEASE Genetic variation in TNFRSF1A is associated with susceptibility to multiple sclerosis 5 (MS5) [MIM:614810]. A multifactorial, inflammatory, demyelinating disease of the central nervous system. Sclerotic lesions are characterized by perivascular infiltration of monocytes and lymphocytes and appear as indurated areas in pathologic specimens (sclerosis in plaques). The pathological mechanism is regarded as an autoimmune attack of the myelin sheat, mediated by both cellular and humoral immunity. Clinical manifestations include visual loss, extra-ocular movement disorders, paresthesias, loss of sensation, weakness, dysarthria, spasticity, ataxia and bladder dysfunction. Genetic and environmental factors influence susceptibility to the disease. Note=An intronic mutation affecting alternative splicing and skipping of exon 6 directs increased expression of isoform 4 a transcript encoding a C-terminally truncated protein which is secreted and may function as a TNF antagonist.SIMILARITY Contains 1 death domain.SIMILARITY Contains 4 TNFR-Cys repeats.") (DB_ID 66345) (description "recommendedName: Tumor necrosis factor receptor superfamily member 1A alternativeName: Tumor necrosis factor receptor 1 shortName:TNF-R1 alternativeName: Tumor necrosis factor receptor type I shortName:TNF-RI shortName:TNFR-I alternativeName: p55 alternativeName: p60 cdAntigenNameCD120a/cdAntigenName component recommendedName: Tumor necrosis factor receptor superfamily member 1A, membrane form /component component recommendedName: Tumor necrosis factor-binding protein 1 shortName:TBPI /component") (geneName "TNFRSF1A" "TNFAR" "TNFR1") (identifier "P19438") (isSequenceChanged FALSE) (keyword "3D-structure" "Alternative splicing" "Amyloidosis" "Apoptosis" "Cell membrane" "Cleavage on pair of basic residues" "Complete proteome" "Direct protein sequencing" "Disease mutation" "Disulfide bond" "Glycoprotein" "Golgi apparatus" "Host-virus interaction" "Membrane" "Polymorphism" "Receptor" "Reference proteome" "Repeat" "Secreted" "Signal" "Transmembrane" "Transmembrane helix") (name "TNFRSF1A") (referenceDatabase [GK_2]) (secondaryIdentifier "TNR1A_HUMAN" "A8K4X3" "B2RDE4" "B3KPQ1" "B4DQB7" "B4E309" "D3DUR1" "Q9UCA4") (sequenceLength 455) (species [GK_48887])) ([GK_66370] of EntityWithAccessionedSequence (_displayName "[Hsa] TRAF2 [cytosol]") (compartment [GK_70101]) (DB_ID 66370) (endCoordinate 501) (name "TRAF2" "TNF receptor associated factor 2" "Tumor necrosis factor type 2 receptor associated protein 3") (referenceEntity [GK_66371]) (species [GK_48887]) (stableIdentifier [GK_369343]) (startCoordinate 2)) ([GK_66371] of ReferenceGeneProduct (_displayName "[Hsa] UniProt:Q12933 TRAF2 recommendedName: TNF receptor-associated factor 2 ecNumber6.3.2.-/ecNumber alternativeName: E3 ubiquitin-protein ligase TRAF2 alternativeName: Tumor necrosis factor type 2 receptor-associated protein 3 ") (checksum "C508BE185B783B20") (comment "FUNCTION Regulates activation of NF-kappa-B and JNK and plays a central role in the regulation of cell survival and apoptosis. Required for normal antibody isotype switching from IgM to IgG. Has E3 ubiquitin-protein ligase activity and promotes 'Lys-63'-linked ubiquitination of target proteins, such as BIRC3, RIPK1 and TICAM1. Is an essential constituent of several E3 ubiquitin-protein ligase complexes, where it promotes the ubiquitination of target proteins by bringing them into contact with other E3 ubiquitin ligases. Regulates BIRC2 and BIRC3 protein levels by inhibiting their autoubiquitination and subsequent degradation; this does not depend on the TRAF2 RING-type zinc finger domain.ENZYME REGULATION Has very low E3 ubiquitin ligase activity in the absence of sphingosine-1-phosphate. E3 ubiquitin ligase activity is strongly activated by cytoplasmic sphingosine-1-phosphate.PATHWAY Protein modification; protein ubiquitination.SUBUNIT Homotrimer, and heterotrimer with TRAF1 and TRAF3 (via TRAF domain). The domain containing the RING-type and the first TRAF-type zinc finger can also form homodimers (in vitro). Interacts with TNFRSF1B/TNFR2, TNFRSF4, TNFRSF5/CD40, CD27/TNFRSF7, TNFRSF8/CD30, TNFRSF9/CD137, TNFRSF11A/RANK, TNFRSF13B/TACI, TNFRSF14, TNFRSF16/NGFR, TNFRSF17/BCMA, TNFRSF18/AITR, TNFRSF19/TROY, TNFRSF19L/RELT, XEDAR, EDAR, Epstein-Barr virus BNFL1/LMP-1 and IL15RA. Interacts with CDK9, CSK, MAP3K1, MAP3K5, MAP3K11, MAP3K14, MAP4K2, RIPK1, RIPK2, TNIK, TBK1, SPHK1, TRADD, TRAFD1, TRAIP, TANK/ITRAF, TNFAIP3, TDP2, MAVS/IPS1, TICAM1 and TRPC4AP. Interacts with CASP8AP2, NFATC2IP, PEG3 and HIVEP3 (By similarity). Interacts with BIRC2 and BIRC3 N-terminus; a single BIRC2 or BIRC3 molecule interacts with a heterotrimer formed by TRAF1 and TRAF2, or a TRAF2 homotrimer. Identified in a complex composed of TRAF2, TRAF3, BIRC2 and BIRC3. Interaction with BIRC2 and/or BIRC3 is essential for degradation of NFKBIA and activation of NF-kappa-B. Interacts with CYLD, USP48, DAB2IP, IKKA and IKKB. Identified in a complex with TNFRSF1A, RIPK1 and IKKB. Interacts (via 'Lys-63'-linked polyubiquitin chains) with TAB2 and TAB3. Interacts with ERN1 and TAOK3. Interaction with TAOK3 is facilitated under ER stress conditions, such as treatment with tunicamycin, and may promote TRAF2 phosphorylation.DOMAIN The coiled coil domain mediates homo- and hetero-oligomerization.DOMAIN The MATH/TRAF domain binds to receptor cytoplasmic domains.DOMAIN The RING-type zinc finger domain is essential for E3 ubiquitin-protein ligase activity. It is not essential for the stabilization of BIRC2, or for the ubiquitination of RIPK1 in response to TNFR1 signaling.PTM Phosphorylated at several serine residues within the first 128 amino acid residues. Phosphorylated at Thr-117 in response to signaling via TNF and TNFRSF1A. Phosphorylation at Thr-117 is required for 'Lys-63'-linked polyubiquitination, but not for 'Lys-48'-linked polyubiquitination. Phosphorylation at Thr-117 is important for interaction with IKKA and IKKB, activation of IKK and subsequent activation of NF-kappa-B.PTM Undergoes both 'Lys-48'-linked and 'Lys-63'-linked polyubiquitination. Polyubiquitinated via 'Lys-63'-linked ubiquitin in response to TNF signaling; this requires prior phosphorylation at Thr-117. 'Lys-63'-linked polyubiquitination promotes TRAF2-mediated activation of NF-kappa-B. Can be polyubiquitinated at several Lys residues via 'Lys-48'-linked ubiquitin chains in response to TNF signaling, leading to proteasomal degradation. Autoubiquitinated, leading to its subsequent proteasomal degradation. Polyubiquitinated by BIRC2 and SIAH2, leading to its subsequent proteasomal degradation. Deubiquitinated by CYLD, a protease that specifically cleaves 'Lys-63'-linked polyubiquitin chains.SIMILARITY Belongs to the TNF receptor-associated factor family. A subfamily.SIMILARITY Contains 1 MATH domain.SIMILARITY Contains 1 RING-type zinc finger.SIMILARITY Contains 2 TRAF-type zinc fingers.") (DB_ID 66371) (description "recommendedName: TNF receptor-associated factor 2 ecNumber6.3.2.-/ecNumber alternativeName: E3 ubiquitin-protein ligase TRAF2 alternativeName: Tumor necrosis factor type 2 receptor-associated protein 3 ") (geneName "TRAF2" "TRAP3") (identifier "Q12933") (isSequenceChanged TRUE) (keyword "3D-structure" "Acetylation" "Alternative splicing" "Apoptosis" "Coiled coil" "Complete proteome" "Cytoplasm" "Isopeptide bond" "Ligase" "Lipid-binding" "Metal-binding" "Phosphoprotein" "Reference proteome" "Repeat" "Ubl conjugation" "Ubl conjugation pathway" "Zinc" "Zinc-finger") (name "TRAF2") (referenceDatabase [GK_2]) (secondaryIdentifier "TRAF2_HUMAN" "A8K107" "B4DPJ7" "Q7Z337" "Q96NT2") (sequenceLength 501) (species [GK_48887])) ([GK_66376] of EntityWithAccessionedSequence (_displayName "[Hsa] Tumor necrosis factor receptor type 1 associated DEATH domain protein [cytosol]") (compartment [GK_70101]) (DB_ID 66376) (endCoordinate 312) (name "Tumor necrosis factor receptor type 1 associated DEATH domain protein" "TNFR1-associated DEATH domain protein" "TNFRSF1A-associated via death domain") (referenceEntity [GK_66377]) (species [GK_48887]) (stableIdentifier [GK_365494]) (startCoordinate 1)) ([GK_66377] of ReferenceGeneProduct (_displayName "[Hsa] UniProt:Q15628 TRADD recommendedName: Tumor necrosis factor receptor type 1-associated DEATH domain protein shortName:TNFR1-associated DEATH domain protein alternativeName: TNFRSF1A-associated via death domain ") (checksum "5645D7E63E5FF05A") (comment "FUNCTION The nuclear form acts as a tumor suppressor by preventing ubiquitination and degradation of isoform p19ARF/ARF of CDKN2A by TRIP12: acts by interacting with TRIP12, leading to disrupt interaction between TRIP12 and isoform p19ARF/ARF of CDKN2A (By similarity). Adapter molecule for TNFRSF1A/TNFR1 that specifically associates with the cytoplasmic domain of activated TNFRSF1A/TNFR1 mediating its interaction with FADD. Overexpression of TRADD leads to two major TNF-induced responses, apoptosis and activation of NF-kappa-B.SUBUNIT Interacts with TRIP12 (By similarity). Heterodimer with TNFRSF1A/TNFR1. Interacts with DAB2IP, FADD, HIPK2, KRT14, KRT16, KRT17, KRT18, RIPK1, SQSTM1, TRAF1, TRAF2 and TRPC4AP.TISSUE SPECIFICITY Found in all examined tissues.DOMAIN Requires the intact death domain to associate with TNFRSF1A/TNFR1.SIMILARITY Contains 1 death domain.") (DB_ID 66377) (description "recommendedName: Tumor necrosis factor receptor type 1-associated DEATH domain protein shortName:TNFR1-associated DEATH domain protein alternativeName: TNFRSF1A-associated via death domain ") (geneName "TRADD") (identifier "Q15628") (isSequenceChanged FALSE) (keyword "3D-structure" "Apoptosis" "Complete proteome" "Cytoplasm" "Cytoskeleton" "Nucleus" "Reference proteome") (name "TRADD") (referenceDatabase [GK_2]) (secondaryIdentifier "TRADD_HUMAN" "B2RDS3" "Q52NZ1") (sequenceLength 312) (species [GK_48887])) ([GK_66401] of ReferenceGeneProduct (_displayName "[Hsa] UniProt:P02788 LTF Lactotransferrin shortName:Lactoferrin alternativeName: Talalactoferrin component recommendedName: Kaliocin-1 /component component recommendedName: Lactoferroxin-A /component component recommendedName: Lactoferroxin-B /component component recommendedName: Lactoferroxin-C /component") (checksum "1") (comment "CATALYTIC ACTIVITY Preferential at -Arg-Ser-Arg-Arg-|- and -Arg-Arg-Ser-Arg-|-, and of Z-Phe-Arg-|-aminomethylcoumarin.SUBUNIT Monomer.SIMILARITY Belongs to the transferrin family.SIMILARITY Contains 2 transferrin-like domains.") (DB_ID 66401) (description " Lactotransferrin shortName:Lactoferrin alternativeName: Talalactoferrin component recommendedName: Kaliocin-1 /component component recommendedName: Lactoferroxin-A /component component recommendedName: Lactoferroxin-B /component component recommendedName: Lactoferroxin-C /component") (geneName "LTF" "LF") (identifier "P02788") (isSequenceChanged TRUE) (keyword "3D-structure" "Antibiotic" "Antimicrobial" "Complete proteome" "Direct protein sequencing" "Disulfide bond" "Glycoprotein" "Hydrolase" "Ion transport" "Iron" "Iron transport" "Metal-binding" "Phosphoprotein" "Polymorphism" "Protease" "Repeat" "Secreted" "Serine protease" "Signal" "Transport") (name "LTF") (referenceDatabase [GK_2]) (secondaryIdentifier "TRFL_HUMAN" "O00756" "Q16780" "Q16785" "Q16786" "Q16789" "Q8IU92" "Q8IZH6" "Q8TCD2" "Q96KZ4" "Q96KZ5" "Q9H1Z3" "Q9UCY5") (sequenceLength 710) (species [GK_48887])) ([GK_66545] of ReferenceGeneProduct (_displayName "[Hsa] UniProt:P02766 TTR recommendedName: Transthyretin alternativeName: ATTR alternativeName: Prealbumin alternativeName: TBPA ") (checksum "1") (comment "DOMAIN Each monomer has two 4-stranded beta sheets and the shape of a prolate ellipsoid. Antiparallel beta-sheet interactions link monomers into dimers. A short loop from each monomer forms the main dimer-dimer interaction. These two pairs of loops separate the opposed, convex beta-sheets of the dimers to form an internal channel.MISCELLANEOUS Tetramer dissociation and partial unfolding leads to the formation of aggregates and amyloid fibrils. Small molecules that occupy at least one of the thyroid hormone binding sites stabilize the tetramer, and thereby stabilize the native state and protect against misfolding and the formation of amyloid fibrils.MISCELLANEOUS Two binding sites for thyroxine are located in the channel. Less than 1% of plasma prealbumin molecules are normally involved in thyroxine transport. L-thyroxine binds to the transthyretin by an order of magnitude stronger than does the triiodo-L-thyronine. Thyroxine-binding globulin is the major carrier protein for thyroid hormones in man.MISCELLANEOUS About 40% of plasma transthyretin circulates in a tight protein-protein complex with the plasma retinol-binding protein (RBP). The formation of the complex with RBP stabilizes the binding of retinol to RBP and decreases the glomerular filtration and renal catabolism of the relatively small RBP molecule. There is evidence for 2 binding sites for RBP, one possibly being a region that includes Ile-104, located on the outer surface of the transthyretin molecule.SIMILARITY Belongs to the transthyretin family.") (DB_ID 66545) (description "recommendedName: Transthyretin alternativeName: ATTR alternativeName: Prealbumin alternativeName: TBPA ") (geneName "TTR" "PALB") (identifier "P02766") (isSequenceChanged TRUE) (keyword "3D-structure" "Amyloid" "Amyloidosis" "Complete proteome" "Cytoplasm" "Direct protein sequencing" "Disease mutation" "Gamma-carboxyglutamic acid" "Glycoprotein" "Hormone" "Neuropathy" "Polymorphism" "Secreted" "Signal" "Thyroid hormone" "Transport") (name "TTR") (referenceDatabase [GK_2]) (secondaryIdentifier "TTHY_HUMAN" "Q549C7" "Q6IB96" "Q9UBZ6" "Q9UCM9") (sequenceLength 147) (species [GK_48887])) ([GK_69324] of Affiliation (_displayName "NYU School of Medicine, Department of Biochemistry") (address "New York NY USA") (DB_ID 69324) (name "NYU School of Medicine, Department of Biochemistry")) ([GK_69416] of Pathway (_displayName "[Hsa] Dimerization of procaspase-8") (_doRelease TRUE) (compartment [GK_356]) (DB_ID 69416) (edited [GK_2671826]) (goBiologicalProcess [GK_23175]) (hasEvent [GK_73945] [GK_141156] [GK_141159]) (literatureReference [GK_1267800] [GK_2584573] [GK_2671825]) (name "Dimerization of procaspase-8") (reviewed [GK_2594924]) (species [GK_48887]) (stableIdentifier [GK_358384]) (summation [GK_213104])) ([GK_69781] of ReferenceGeneProduct (_displayName "[Hsa] UniProt:P05067 APP recommendedName: Amyloid beta A4 protein alternativeName: ABPP alternativeName: APPI shortName:APP alternativeName: APPI shortName:APP alternativeName: Alzheimer disease amyloid protein alternativeName: Cerebral vascular amyloid peptide shortName:CVAP alternativeName: Cerebral vascular amyloid peptide shortName:CVAP alternativeName: PreA4 alternativeName: Protease nexin-II shortName:PN-II alternativeName: Protease nexin-II shortName:PN-II component recommendedName: N-APP /component component recommendedName: Soluble APP-alpha shortName:S-APP-alpha /component component recommendedName: Soluble APP-beta shortName:S-APP-beta /component component recommendedName: C99 /component component recommendedName: Beta-amyloid protein 42 alternativeName: Beta-APP42 /component component recommendedName: Beta-amyloid protein 40 alternativeName: Beta-APP40 /component component recommendedName: C83 /component component recommendedName: P3(42) /component component recommendedName: P3(40) /component component recommendedName: C80 /component component recommendedName: Gamma-secretase C-terminal fragment 59 alternativeName: Amyloid intracellular domain 59 shortName:AICD-59 shortName:AID(59) alternativeName: Gamma-CTF(59) /component component recommendedName: Gamma-secretase C-terminal fragment 57 alternativeName: Amyloid intracellular domain 57 shortName:AICD-57 shortName:AID(57) alternativeName: Gamma-CTF(57) /component component recommendedName: Gamma-secretase C-terminal fragment 50 alternativeName: Amyloid intracellular domain 50 shortName:AICD-50 shortName:AID(50) alternativeName: Gamma-CTF(50) /component component recommendedName: C31 /component") (checksum "1") (comment "INDUCTION Increased levels during neuronal differentiation.PTM Proteolytically processed under normal cellular conditions. Cleavage either by alpha-secretase, beta-secretase or theta-secretase leads to generation and extracellular release of soluble APP peptides, S-APP-alpha and S-APP-beta, and the retention of corresponding membrane-anchored C-terminal fragments, C80, C83 and C99. Subsequent processing of C80 and C83 by gamma-secretase yields P3 peptides. This is the major secretory pathway and is non-amyloidogenic. Alternatively, presenilin/nicastrin-mediated gamma-secretase processing of C99 releases the amyloid beta proteins, amyloid-beta 40 (Abeta40) and amyloid-beta 42 (Abeta42), major components of amyloid plaques, and the cytotoxic C-terminal fragments, gamma-CTF(50), gamma-CTF(57) and gamma-CTF(59).PTM Extracellular binding and reduction of copper, results in a corresponding oxidation of Cys-144 and Cys-158, and the formation of a disulfide bond. In vitro, the APP-Cu(+) complex in the presence of hydrogen peroxide results in an increased production of beta-amyloid-containing peptides.PTM Beta-amyloid peptides are degraded by IDE.MISCELLANEOUS Chelation of metal ions, notably copper, iron and zinc, can induce histidine-bridging between beta-amyloid molecules resulting in beta-amyloid-metal aggregates. The affinity for copper is much higher than for other transient metals and is increased under acidic conditions. Extracellular zinc-binding increases binding of heparin to APP and inhibits collagen-binding.SIMILARITY Belongs to the APP family.SIMILARITY Contains 1 BPTI/Kunitz inhibitor domain.") (DB_ID 69781) (description "recommendedName: Amyloid beta A4 protein alternativeName: ABPP alternativeName: APPI shortName:APP alternativeName: APPI shortName:APP alternativeName: Alzheimer disease amyloid protein alternativeName: Cerebral vascular amyloid peptide shortName:CVAP alternativeName: Cerebral vascular amyloid peptide shortName:CVAP alternativeName: PreA4 alternativeName: Protease nexin-II shortName:PN-II alternativeName: Protease nexin-II shortName:PN-II component recommendedName: N-APP /component component recommendedName: Soluble APP-alpha shortName:S-APP-alpha /component component recommendedName: Soluble APP-beta shortName:S-APP-beta /component component recommendedName: C99 /component component recommendedName: Beta-amyloid protein 42 alternativeName: Beta-APP42 /component component recommendedName: Beta-amyloid protein 40 alternativeName: Beta-APP40 /component component recommendedName: C83 /component component recommendedName: P3(42) /component component recommendedName: P3(40) /component component recommendedName: C80 /component component recommendedName: Gamma-secretase C-terminal fragment 59 alternativeName: Amyloid intracellular domain 59 shortName:AICD-59 shortName:AID(59) alternativeName: Gamma-CTF(59) /component component recommendedName: Gamma-secretase C-terminal fragment 57 alternativeName: Amyloid intracellular domain 57 shortName:AICD-57 shortName:AID(57) alternativeName: Gamma-CTF(57) /component component recommendedName: Gamma-secretase C-terminal fragment 50 alternativeName: Amyloid intracellular domain 50 shortName:AICD-50 shortName:AID(50) alternativeName: Gamma-CTF(50) /component component recommendedName: C31 /component") (geneName "APP" "A4" "AD1") (identifier "P05067") (isSequenceChanged TRUE) (keyword "3D-structure" "Alternative splicing" "Alzheimer disease" "Amyloid" "Amyloidosis" "Apoptosis" "Cell adhesion" "Coated pit" "Complete proteome" "Copper" "Direct protein sequencing" "Disease mutation" "Disulfide bond" "Endocytosis" "Glycoprotein" "Heparin-binding" "Iron" "Membrane" "Metal-binding" "Neurodegeneration" "Notch signaling pathway" "Phosphoprotein" "Polymorphism" "Protease inhibitor" "Proteoglycan" "Serine protease inhibitor" "Signal" "Transmembrane" "Transmembrane helix" "Zinc") (name "APP") (referenceDatabase [GK_2]) (secondaryIdentifier "A4_HUMAN" "B2R5V1" "D3DSD1" "D3DSD2" "D3DSD3" "P09000" "P78438" "Q13764" "Q13778" "Q13793" "Q16011" "Q16014" "Q16019" "Q16020" "Q6GSC0" "Q8WZ99" "Q9BT38" "Q9UC33" "Q9UCA9" "Q9UCB6" "Q9UCC8" "Q9UCD1" "Q9UQ58") (sequenceLength 770) (species [GK_48887])) ([GK_70101] of EntityCompartment (_displayName "cytosol") (accession "0005829") (DB_ID 70101) (definition "The part of the cytoplasm that does not contain organelles but which does contain other particulate matter, such as protein complexes.") 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DatabaseIdentifier (_displayName "NCBI_taxonomy:9605") (DB_ID 72948) (identifier "9605") (referenceDatabase [GK_72810])) ([GK_73681] of Person (_displayName "Gillespie, ME") (affiliation [GK_77249] [GK_158007]) (DB_ID 73681) (eMailAddress "gillespm@cshl.org") (firstname "Marc E") (initial "ME") (surname "Gillespie")) ([GK_73887] of Pathway (_displayName "[Hsa] Death Receptor Signalling") (_doRelease TRUE) (authored [GK_139957]) (compartment [GK_356]) (DB_ID 73887) (edited [GK_165085]) (goBiologicalProcess [GK_25446]) (hasEvent [GK_75157] [GK_75893] [GK_75158]) (name "Death Receptor Signalling") (reviewed [GK_165094]) (species [GK_48887]) (stableIdentifier [GK_361140]) (summation [GK_139958])) ([GK_73945] of Reaction (_displayName "[Hsa] FAS-mediated dimerization of procaspase-8") (_doRelease TRUE) (compartment [GK_876] [GK_70101]) (DB_ID 73945) (edited [GK_2671826]) (figure [GK_141227]) (input [GK_75114] [GK_57031]) (literatureReference [GK_141158] [GK_2984185] [GK_1267807]) (name "FAS-mediated dimerization of procaspase-8") (output [GK_2671811]) (precedingEvent [GK_83586]) (reviewed [GK_2594924]) (species [GK_48887]) (stableIdentifier [GK_359070]) (summation [GK_178760])) ([GK_74112] of SimpleEntity (_displayName "Ca2+ [extracellular region]") (compartment [GK_984]) (crossReference [GK_29497]) (DB_ID 74112) (name "Ca2+" "Calcium") (referenceEntity [GK_114768]) (stableIdentifier [GK_363887])) ([GK_74277] of Complex (_displayName "[Hsa] TNF-alpha:TNF-R1 complex [plasma membrane]") (compartment [GK_876]) (DB_ID 74277) (hasComponent [GK_66220] [GK_66344]) (name "TNF-alpha:TNF-R1 complex") (species [GK_48887]) (stableIdentifier [GK_367488])) ([GK_74302] of Summation (_displayName "Once the TNF-aplha:TNF-R1:TRADD complex is formed the two TN...") (DB_ID 74302) (text "Once the TNF-aplha:TNF-R1:TRADD complex is formed the two TNF-alpha mediated pathways are possible. The variable is the recruitment of FADD to the larger complex formed by the TNF-aplha:TNF-R1 platform via the interaction of the Death Domains. The steps leading to the Jun, NF kappaB, or apoptotic pathways are rife with modulation.")) ([GK_74353] of Summation (_displayName "Once formed the TRADD:TRAF2:RIP1 complex may dissociate from...") (DB_ID 74353) (text "Once formed the TRADD:TRAF2:RIP1 complex may dissociate from the TNF:TNF-R1 platform and become cytosolic. If this complex recruits FADD then the cell will be pushed along the apoptotic pathway.")) ([GK_75114] of Complex (_displayName "[Hsa] FASL:FAS Receptor Trimer:FADD:pro-Caspase-8 DISC [plasma membrane]") (compartment [GK_876]) (DB_ID 75114) (hasComponent [GK_43124] [GK_57031]) (name "FASL:FAS Receptor Trimer:FADD:pro-Caspase-8 DISC") (species [GK_48887]) (stableIdentifier [GK_362769])) ([GK_75146] of Reaction (_displayName "[Hsa] TRAIL:TRAIL-Receptor2 Trimer:FADD complex binds Caspase-8") (_doRelease TRUE) (compartment [GK_876] [GK_70101]) (DB_ID 75146) (input [GK_57031] [GK_141137]) (literatureReference [GK_141128]) (name "TRAIL:TRAIL-Receptor2 Trimer:FADD complex binds Caspase-8") (output [GK_141133]) (precedingEvent [GK_75187]) (species [GK_48887]) (stableIdentifier [GK_359034]) (summation [GK_179247])) ([GK_75157] of Pathway (_displayName "[Hsa] FasL/ CD95L signaling") (_doRelease TRUE) (authored [GK_140480]) (compartment [GK_356]) (DB_ID 75157) (edited [GK_165085]) (figure [GK_141234]) (goBiologicalProcess [GK_25446]) (hasEvent [GK_75244] [GK_71050] [GK_83650] [GK_83586] [GK_141310]) (literatureReference [GK_139960]) (name "FasL/ CD95L signaling") (reviewed [GK_165094]) (species [GK_48887]) (stableIdentifier [GK_360947]) (summation [GK_140481])) ([GK_75158] of Pathway (_displayName "[Hsa] TRAIL signaling") (_doRelease TRUE) (authored [GK_141084]) (compartment [GK_356]) (DB_ID 75158) (edited [GK_165085]) (hasEvent [GK_75238] [GK_141139] [GK_75187] [GK_75146] [GK_141316]) (literatureReference [GK_140992]) (name "TRAIL signaling") (species [GK_48887]) (stableIdentifier [GK_358827]) (summation [GK_141083])) ([GK_75187] of Reaction (_displayName "[Hsa] TRAIL:TRAIL receptor-2 Trimer Binds FADD") (_doRelease TRUE) (compartment [GK_876] [GK_70101]) (DB_ID 75187) (input [GK_141126] [GK_54639]) (literatureReference [GK_141128]) (name "TRAIL:TRAIL receptor-2 Trimer Binds FADD") (output [GK_141137]) (precedingEvent [GK_75238]) (species [GK_48887]) (stableIdentifier [GK_362019]) (summation [GK_179245])) ([GK_75238] of Reaction (_displayName "[Hsa] TRAIL Binds TRAIL-Receptor2") (_doRelease TRUE) (compartment [GK_876] [GK_984]) (DB_ID 75238) (input [GK_66186] [GK_65505]) (literatureReference [GK_141147]) (name "TRAIL Binds TRAIL-Receptor2") (output [GK_141118]) (species [GK_48887]) (stableIdentifier [GK_358527]) (summation [GK_179243])) ([GK_75240] of Reaction (_displayName "[Hsa] TRADD:TRAF2:RIP1:FADD complex binds Pro-Caspase 8 ") (_doRelease TRUE) (compartment [GK_70101]) (DB_ID 75240) (input [GK_57031] [GK_140977]) (literatureReference [GK_140979]) (name "TRADD:TRAF2:RIP1:FADD complex binds Pro-Caspase 8 ") (output [GK_140976]) (precedingEvent [GK_140978]) (species [GK_48887]) (stableIdentifier [GK_360371]) (summation [GK_179240])) ([GK_75244] of Reaction (_displayName "[Hsa] FASL binds FAS Receptor") (_doRelease TRUE) (compartment [GK_876] [GK_984]) (DB_ID 75244) (figure [GK_141237]) (goBiologicalProcess [GK_25446]) (input [GK_66212] [GK_66248]) (literatureReference [GK_140513]) (name "FASL binds FAS Receptor") (output [GK_76564]) (species [GK_48887]) (stableIdentifier [GK_361795]) (summation [GK_178761])) ([GK_75542] of Person (_displayName "Teplow, DB") (DB_ID 75542) (firstname "D B") (initial "DB") (surname "Teplow")) ([GK_75579] of Person (_displayName "Klisak, I") (DB_ID 75579) (firstname "I") (initial "I") (surname "Klisak")) ([GK_75582] of Person (_displayName "Mohandas, T") (DB_ID 75582) (firstname "T") (initial "T") (surname "Mohandas")) ([GK_75583] of Person (_displayName "Sparkes, RS") (DB_ID 75583) (firstname "R S") (initial "RS") (surname "Sparkes")) ([GK_75642] of Person (_displayName "Lem, J") (DB_ID 75642) (firstname "Janis") (initial "J") (surname "Lem")) ([GK_75643] of Person (_displayName "Simon, M") (DB_ID 75643) (firstname "Melvin") (initial "M") (surname "Simon")) ([GK_75697] of Person (_displayName "Goeddel, DV") (DB_ID 75697) (firstname "D V") (initial "DV") (surname "Goeddel")) ([GK_75893] of Pathway (_displayName "[Hsa] TNF signaling") (_doRelease TRUE) (authored [GK_140936]) (compartment [GK_356]) (DB_ID 75893) (edited [GK_165085]) (hasEvent [GK_83660] [GK_83656] [GK_83582] [GK_140978] [GK_75240]) (literatureReference [GK_140939]) (name "TNF signaling") (species [GK_48887]) (stableIdentifier [GK_361228]) (summation [GK_140942])) ([GK_75975] of EntityWithAccessionedSequence (_displayName "[Hsa] p18 subunit of Caspase 8 [cytosol]") (compartment [GK_70101]) (DB_ID 75975) (endCoordinate 374) (name "p18 subunit of Caspase 8") (referenceEntity [GK_57032]) (species [GK_48887]) (stableIdentifier [GK_365034]) (startCoordinate 217)) ([GK_76158] of EntityWithAccessionedSequence (_displayName "[Hsa] p10 subunit of Caspase 8 [cytosol]") (compartment [GK_70101]) (DB_ID 76158) (endCoordinate 479) (name "p10 subunit of Caspase 8") (referenceEntity [GK_57032]) (species [GK_48887]) (stableIdentifier [GK_367761]) (startCoordinate 385)) ([GK_76195] of Complex (_displayName "[Hsa] FASL:FAS Receptor Trimer [plasma membrane]") (compartment [GK_876]) (DB_ID 76195) (hasComponent [GK_76564] [GK_76564] [GK_76564]) (name "FASL:FAS Receptor Trimer") (species [GK_48887]) (stableIdentifier [GK_371020])) ([GK_76564] of Complex (_displayName "[Hsa] FASL:FAS Receptor monomer [plasma membrane]") (compartment [GK_876]) (DB_ID 76564) (hasComponent [GK_66212] [GK_66248]) (name "FASL:FAS Receptor monomer") (species [GK_48887]) (stableIdentifier [GK_365522])) ([GK_76786] of Person (_displayName "Seto, Y") (DB_ID 76786) (firstname "Y") (initial "Y") (surname "Seto")) ([GK_77151] of Person (_displayName "el-Deiry, WS") (DB_ID 77151) (firstname "W S") (initial "WS") (surname "el-Deiry")) ([GK_77249] of Affiliation (_displayName "St. John's University") (address "8000 Utopia Parkway") (DB_ID 77249) (name "St. John's University")) ([GK_77293] of Person (_displayName "Tschopp, J") (affiliation [GK_157508]) (DB_ID 77293) (eMailAddress "jtschopp@mail-eliot.unil.ch") (firstname "Jurg") (initial "J") (surname "Tschopp")) ([GK_80155] of GO_CellularComponent (_displayName "host cell 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(instanceOf [GK_259434]) (name "host cell cytoplasm") (referenceDatabase [GK_1])) ([GK_83582] of Reaction (_displayName "[Hsa] TRADD:TRAF2:RIP1 complex dissociates from the TNF-alpha:TNF-R1 complex.") (_doRelease TRUE) (compartment [GK_876] [GK_70101]) (DB_ID 83582) (edited [GK_165085]) (input [GK_140946]) (literatureReference [GK_140979]) (name "TRADD:TRAF2:RIP1 complex dissociates from the TNF-alpha:TNF-R1 complex.") 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region]") (compartment [GK_984]) (DB_ID 976905) (endCoordinate 866) (hasModifiedResidue [GK_976902]) (literatureReference [GK_976921]) (name "Variant fibrinogen alpha chain") (referenceEntity [GK_54840]) (species [GK_48887]) (stableIdentifier [GK_1358175]) (startCoordinate 20)) ([GK_976906] of Person (_displayName "Sletten, K") (DB_ID 976906) (initial "K") (surname "Sletten")) ([GK_976907] of Person (_displayName "Booth, DR") (DB_ID 976907) (initial "DR") (surname "Booth")) ([GK_976908] of LiteratureReference (_displayName "Serum amyloid A protein in amyloidosis, rheumatic, and enoplastic diseases") (author [GK_976904] [GK_976747]) (DB_ID 976908) (journal "Arthritis Rheum") (pages "36-42") (pubMedIdentifier 103558) (title "Serum amyloid A protein in amyloidosis, rheumatic, and enoplastic diseases") (volume 22) (year 1979)) ([GK_976909] of Person (_displayName "Thorsteinsson, L") (DB_ID 976909) (initial "L") (surname "Thorsteinsson")) ([GK_976910] of Person (_displayName "Révész, T") 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te...") (DB_ID 976914) (text "The ABri and ADan peptides are extensions of the normal C terminus of ITM2B (BRI). The sequence of ABri results from mutatin of the normal stop codon to R, resulting in an additional 11 residues. The ABri peptide is the last 34 residues of this mutated peptide - EASNCFAIRHFENKFAVETLICSRTVKKNIIEEN.\nThe ADan peptide is the result of a 10 nucleotide insertion between the codons for residue 265 and 266, introducing a frameshift that adds a different extension to the normal peptide. The ADan peptide is the last 34 residues of this mutated peptide, identical to ABri for the first 22 residues.\n\nEASNCFAIRHFENKFAVETLICFNLFLNSQEKHY ")) ([GK_976915] of Person (_displayName "Plant, G") (DB_ID 976915) (initial "G") (surname "Plant")) ([GK_976916] of Polymer (_displayName "[Hsa] Variant apolipoprotein AII fibril [extracellular region]") (compartment [GK_984]) (DB_ID 976916) (literatureReference [GK_976913]) (name "Variant apolipoprotein AII fibril") (repeatedUnit [GK_976870]) (species [GK_48887]) (stableIdentifier [GK_1358575])) ([GK_976917] of Person (_displayName "Wetzel, R") (DB_ID 976917) (initial "R") (surname "Wetzel")) ([GK_976918] of Person (_displayName "Hong, DP") (DB_ID 976918) (initial "DP") (surname "Hong")) ([GK_976919] of Polymer (_displayName "[Hsa] Gelsolin amyloid fibril [extracellular region]") (compartment [GK_984]) (DB_ID 976919) (literatureReference [GK_976852]) (name "Gelsolin amyloid fibril") (repeatedUnit [GK_976940]) (species [GK_48887]) (stableIdentifier [GK_1358387])) ([GK_976920] of Summation (_displayName "Amyloid is a term used to describe typically extracellular d...") (DB_ID 976920) (literatureReference [GK_977172] [GK_1247722] [GK_1247762] [GK_1247745] [GK_1247696] [GK_1247719] [GK_1247704] [GK_1247703] [GK_1247812] [GK_1247715] [GK_1247805]) (text "Amyloid is a term used to describe typically extracellular deposits of aggregated proteins, sometimes known as plaques. Abnormal accumulation of amyloid is amyloidosis, a term associated with diseased organs and tissues, particularly neurodegenerative diseases such as Alzheimer's, Parkinson's and Huntingdon's. Amyloid deposits consist predominantly of amyloid fibrils, rigid, non-branching structures that form ordered assemblies, characteristically with a cross beta-sheet structure where the sheets run parallel to the direction of the fibril (Sawaya et al. 2007). Often the fibril has a left-handed twist (Nelson & Eisenberg 2006). At least 27 human proteins form amyloid fibrils (Sipe et al. 2010). Many of these proteins have non-pathological functions; the trigger that leads to abnormal aggregations differs between proteins and is not well understood but in many cases the peptides are abnormal fragments or mutant forms arising from polymorphisms, suggesting that the initial event may be aggregation of misfolded or unfolded peptides. Early studies of Amyloid-Beta assembly led to a widely accepted model that assembly was a nucleation-dependent polymerization reaction (Teplow 1998) but it is now understood to be more complex, with multiple 'off-pathway' events leading to a variety of oligomeric structures in addition to fibrils (Roychaudhuri et al. 2008). An increasing body of evidence suggests that these oligomeric forms are primarily responsible for the neurotoxic effects of Amyloid-beta (Roychaudhuri et al. 2008), alpha-synuclein (Winner et al. 2011) and tau (Dance & Strobel 2009, Meraz-Rios et al. 2010). Amyloid oligomers are believed to have a common structural motif that is independent of the protein involved and not present in fibrils (Kayed et al. 2003). Conformation dependent, aggregation specific antibodies suggest that there are 3 general classes of amyloid oligomer structures (Glabe 2009) including annular structures which may be responsible for the widely reported membrane permeabilization effect of amyloid oligomers. Toxicity of amyloid oligomers preceeds the appearance of plaques in mouse models (Ferretti et al. 2011). \nFibrils are often associated with other molecules, notably heparan sulfate proteoglycans and Serum Amyloid P-component, which are universally associated and seem to stabilize fibrils, possibly by protecting them from degradation.")) 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"L-threonine residue 74 replaced with unknown") (coordinate 74) (DB_ID 976926) (psiMod [GK_611082]) (referenceSequence [GK_58841])) ([GK_976927] of Person (_displayName "Uemichi, T") (DB_ID 976927) (initial "T") (surname "Uemichi")) ([GK_976928] of Person (_displayName "Frangione, B") (DB_ID 976928) (initial "B") (surname "Frangione")) ([GK_976929] of Polymer (_displayName "[Hsa] Transthyretin fibril [extracellular region]") (compartment [GK_984]) (DB_ID 976929) (literatureReference [GK_976924]) (name "Transthyretin fibril") (repeatedUnit [GK_976883]) (species [GK_48887]) (stableIdentifier [GK_1358552])) ([GK_976930] of Person (_displayName "Correa, R") (DB_ID 976930) (initial "R") (surname "Correa")) ([GK_976931] of Person (_displayName "Hamidi Asl, K") (DB_ID 976931) (initial "K") (surname "Hamidi Asl")) ([GK_976932] of Person (_displayName "Kluve-Beckerman, B") (DB_ID 976932) (initial "B") (surname "Kluve-Beckerman")) ([GK_976933] of Person (_displayName "Palsdottir, A") (DB_ID 976933) (initial "A") (surname "Palsdottir")) ([GK_976934] of Person (_displayName "Blake, CC") (DB_ID 976934) (initial "CC") (surname "Blake")) ([GK_976935] of Polymer (_displayName "[Hsa] Variant cystatin-C fibril [extracellular region]") (compartment [GK_984]) (DB_ID 976935) (name "Variant cystatin-C fibril") (repeatedUnit [GK_976891]) (species [GK_48887]) (stableIdentifier [GK_1357844])) ([GK_976936] of Person (_displayName "Vigushin, DM") (DB_ID 976936) (initial "DM") (surname "Vigushin")) ([GK_976937] of LiteratureReference (_displayName "Structural stability of amyloid fibrils of beta(2)-microglobulin in comparison with its native fold") (author [GK_976900] [GK_976880]) (DB_ID 976937) (journal "Biochim Biophys Acta") (pages "64-75") (pubMedIdentifier 16213801) (title "Structural stability of amyloid fibrils of beta(2)-microglobulin in comparison with its native fold") (volume 1753) (year 2005)) ([GK_976938] of Person (_displayName "Grubb, A") (DB_ID 976938) (initial "A") (surname "Grubb")) ([GK_976939] of LiteratureReference (_displayName "A stop-codon mutation in the BRI gene associated with familial British dementia") (author [GK_976901] [GK_976928] [GK_976897] [GK_976895] [GK_976910] [GK_976915] [GK_976876]) (DB_ID 976939) (journal "Nature") (pages "776-81") (pubMedIdentifier 10391242) (title "A stop-codon mutation in the BRI gene associated with familial British dementia") (volume 399) (year 1999)) ([GK_976940] of EntityWithAccessionedSequence (_displayName "[Hsa] Gelsolin amyloid fragment [extracellular region]") (compartment [GK_984]) (DB_ID 976940) (endCoordinate 270) (name "Gelsolin amyloid fragment") (referenceEntity [GK_55564]) (species [GK_48887]) (stableIdentifier [GK_1358177]) (startCoordinate 200)) ([GK_976941] of LiteratureReference (_displayName "Variant apolipoprotein AI as a major constituent of a human hereditary amyloid") (author [GK_947995] [GK_976853] [GK_976864] [GK_976904]) (DB_ID 976941) (journal "Biochem Biophys Res Commun") (pages "762-8") (pubMedIdentifier 3142462) (title "Variant apolipoprotein AI as a major constituent of a human hereditary amyloid") (volume 156) (year 1988)) ([GK_976942] of LiteratureReference (_displayName "A new human hereditary amyloidosis: the result of a stop-codon mutation in the apolipoprotein AII gene") (author [GK_976904] [GK_976874] [GK_976886] [GK_194488] [GK_976931] [GK_976861] [GK_976932]) (DB_ID 976942) (journal "Genomics") (pages "272-7") (pubMedIdentifier 11401442) (title "A new human hereditary amyloidosis: the result of a stop-codon mutation in the apolipoprotein AII gene") (volume 72) (year 2001)) ([GK_976943] of Person (_displayName "Arnason, A") (DB_ID 976943) (initial "A") (surname "Arnason")) ([GK_976944] of EntityWithAccessionedSequence (_displayName "[Hsa] Variant lysozyme C [extracellular region]") (compartment [GK_984]) (DB_ID 976944) (endCoordinate 148) (hasModifiedResidue [GK_976926]) (literatureReference [GK_976877]) (name "Variant lysozyme C" "LYZ" 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(title "Isolated atrial amyloid contains atrial natriuretic peptide: a report of six cases") (volume 56) (year 1986)) ([GK_976968] of LiteratureReference (_displayName "Unraveling the amyloid associated with human medullary thyroid carcinoma") (author [GK_976988] [GK_976957] [GK_976972] [GK_976969] [GK_976971] [GK_976989] [GK_976992]) (DB_ID 976968) (journal "Endocrinology") (pages "5465-70") (pubMedIdentifier 15459123) (title "Unraveling the amyloid associated with human medullary thyroid carcinoma") (volume 145) (year 2004)) ([GK_976969] of Person (_displayName "Verma, N") (DB_ID 976969) (initial "N") (surname "Verma")) ([GK_976970] of LiteratureReference (_displayName "Amyloid fibrils in human insulinoma and islets of Langerhans of the diabetic cat are derived from a neuropeptide-like protein also present in normal islet cells") (author [GK_976884] [GK_163570] [GK_976979] [GK_976958] [GK_976961] [GK_976995]) (DB_ID 976970) (journal "Proc Natl Acad Sci U S A") (pages "3881-5") 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(pubMedIdentifier 17190616) (title "Structural models of amyloid-like fibrils") (volume 73) (year 2006)) ([GK_977173] of Person (_displayName "Häggqvist, B") (DB_ID 977173) (initial "B") (surname "Häggqvist")) ([GK_977174] of Summation (_displayName "In addition to the main fibril peptide, mature amyloid fibri...") 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