BioPAX pathway converted from "SMAC, XIAP-regulated apoptotic response" in the Reactome database.SMAC, XIAP-regulated apoptotic responseOnce released from the mitochondria, SMAC binds to IAP family proteins displacing them from Caspase:IAP complexes liberating the active caspases.Authored: Matthews, L, 2004-08-06 15:00:00Reviewed: Vaux, D, 0000-00-00 00:00:00Edited: Shamovsky, Veronica, 2018-11-07LEFT-TO-RIGHTXIAP binds CASP3X‑linked inhibitor of apoptosis protein (XIAP) suppresses cell death by inhibiting the catalytic activity of caspases (Deveraux QL et al. 1997; Paulsen M et al. 2008). XIAP consists of three bacculoviral inhibitory repeat (BIR) domains and a C‑terminal ring finger. Biochemical and structural analyses revealed that the linker connecting BIR1 to BIR2 inhibits executioner caspase‑3 and ‑7 by positioning itself at the active site (Sun C et al. 1999; Riedl SJ et al. 2001; Huang Y et al. 2001; Chai J et al. 2001). Formation of a complex between caspase‑3 or caspase‑7 and the XIAP BIR2‑linker region appears to be driven by interactions between XIAP's Leu141 and Val146 and a hydrophobic site present on both caspases. This hydrophobic site is not found in caspase‑8 or caspase‑9, perhaps explaining the binding specificity of XIAP (Riedl SJ et al. 2001). BIR2 domain of XIAP may also contribute to inhibition of executioner caspases by interacting with additional sites on the enzymes (Scott FL et al. 2005; Abhari BA & Davoodi J 2008).Authored: Shamovsky, Veronica, 2017-07-26Reviewed: Matthews, Lisa, 2018-11-05Edited: Shamovsky, Veronica, 2018-11-02XIAPBaculoviral IAP repeat-containing protein 4Inhibitor of apoptosis protein 3X-linked inhibitor of apoptosis proteinX-linked IAPIAP-like proteinHILPBIRC4Reactome DB_ID: 50849cytosolGENE ONTOLOGYGO:0005829UniProt:P98170 XIAPXIAPAPI3BIRC4IAP3FUNCTION Multi-functional protein which regulates not only caspases and apoptosis, but also modulates inflammatory signaling and immunity, copper homeostasis, mitogenic kinase signaling, cell proliferation, as well as cell invasion and metastasis. Acts as a direct caspase inhibitor. Directly bind to the active site pocket of CASP3 and CASP7 and obstructs substrate entry. Inactivates CASP9 by keeping it in a monomeric, inactive state. Acts as an E3 ubiquitin-protein ligase regulating NF-kappa-B signaling and the target proteins for its E3 ubiquitin-protein ligase activity include: RIPK1, CASP3, CASP7, CASP8, CASP9, MAP3K2/MEKK2, DIABLO/SMAC, AIFM1, CCS and BIRC5/survivin. Ubiquitinion of CCS leads to enhancement of its chaperone activity toward its physiologic target, SOD1, rather than proteasomal degradation. Ubiquitinion of MAP3K2/MEKK2 and AIFM1 does not lead to proteasomal degradation. Plays a role in copper homeostasis by ubiquitinationg COMMD1 and promoting its proteasomal degradation. Can also function as E3 ubiquitin-protein ligase of the NEDD8 conjugation pathway, targeting effector caspases for neddylation and inactivation. Regulates the BMP signaling pathway and the SMAD and MAP3K7/TAK1 dependent pathways leading to NF-kappa-B and JNK activation. Acts as an important regulator of innate immune signaling via regulation of Nodlike receptors (NLRs). Protects cells from spontaneous formation of the ripoptosome, a large multi-protein complex that has the capability to kill cancer cells in a caspase-dependent and caspase-independent manner. Suppresses ripoptosome formation by ubiquitinating RIPK1 and CASP8. Acts as a positive regulator of Wnt signaling and ubiquitinates TLE1, TLE2, TLE3, TLE4 and AES. Ubiquitination of TLE3 results in inhibition of its interaction with TCF7L2/TCF4 thereby allowing efficient recruitment and binding of the transcriptional coactivator beta-catenin to TCF7L2/TCF4 that is required to initiate a Wnt-specific transcriptional program.SUBUNIT Monomer, and homodimer. Interacts with DIABLO/SMAC and with PRSS25; these interactions inhibit apoptotic suppressor activity. Interacts with TAB1/MAP3K7IP1 and AIFM1. Interaction with SMAC hinders binding of TAB1/MAP3K7IP1 and AIFM1. Interacts with TCF25 and COMMD1. Interacts with SEPTIN4 isoform 6, but not with other SEPTIN4 isoforms. Interacts with RIP1, RIP2, RIP3, RIP4, CCS and USP19. Interacts (via BIR 2 domain and BIR 3 domain) with HAX1 (via C-terminus) and this interaction blocks ubiquitination of XIAP/BIRC4. Interacts with the monomeric form of BIRC5/survivin. Interacts with TLE3 and TCF7L2/TCF4. Interacts (via BIR 3 and RING domains) with PDCL3 (PubMed:19012568).TISSUE SPECIFICITY Ubiquitous, except peripheral blood leukocytes.DOMAIN The first BIR domain is involved in interaction with TAB1/MAP3K7IP1 and is important for dimerization. The second BIR domain is sufficient to inhibit CASP3 and CASP7, while the third BIR is involved in CASP9 inhibition. The interactions with DIABLO/SMAC and PRSS25 are mediated by the second and third BIR domains.PTM S-Nitrosylation down-regulates its E3 ubiquitin-protein ligase activity.PTM Autoubiquitinated and degraded by the proteasome in apoptotic cells.PTM Phosphorylation by PKB/AKT protects XIAP against ubiquitination and protects the protein against proteasomal degradation.SIMILARITY Belongs to the IAP family.Homo sapiensNCBI Taxonomy9606UniProtP981701EQUAL497EQUALReactome Database ID Release 7150849Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=50849ReactomeR-HSA-508492Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-50849.2Reactomehttp://www.reactome.org2Caspase-32x(CASP3(29-175):CASP3(176-277))Reactome DB_ID: 350870Caspase-3 heterodimerCASP3(29-175):CASP3(176-277)Reactome DB_ID: 350888CASP3(176-277)Caspase-3 (small subunit)Reactome DB_ID: 141646UniProt:P42574 CASP3CASP3CPP32FUNCTION Involved in the activation cascade of caspases responsible for apoptosis execution. At the onset of apoptosis it proteolytically cleaves poly(ADP-ribose) polymerase (PARP) at a '216-Asp-|-Gly-217' bond. Cleaves and activates sterol regulatory element binding proteins (SREBPs) between the basic helix-loop-helix leucine zipper domain and the membrane attachment domain. Cleaves and activates caspase-6, -7 and -9. Involved in the cleavage of huntingtin. Triggers cell adhesion in sympathetic neurons through RET cleavage.ACTIVITY REGULATION Inhibited by isatin sulfonamides.SUBUNIT Heterotetramer that consists of two anti-parallel arranged heterodimers, each one formed by a 17 kDa (p17) and a 12 kDa (p12) subunit. Interacts with BIRC6/bruce.TISSUE SPECIFICITY Highly expressed in lung, spleen, heart, liver and kidney. Moderate levels in brain and skeletal muscle, and low in testis. Also found in many cell lines, highest expression in cells of the immune system.PTM Cleavage by granzyme B, caspase-6, caspase-8 and caspase-10 generates the two active subunits. Additional processing of the propeptides is likely due to the autocatalytic activity of the activated protease. Active heterodimers between the small subunit of caspase-7 protease and the large subunit of caspase-3 also occur and vice versa.PTM S-nitrosylated on its catalytic site cysteine in unstimulated human cell lines and denitrosylated upon activation of the Fas apoptotic pathway, associated with an increase in intracellular caspase activity. Fas therefore activates caspase-3 not only by inducing the cleavage of the caspase zymogen to its active subunits, but also by stimulating the denitrosylation of its active site thiol.SIMILARITY Belongs to the peptidase C14A family.UniProtP42574176EQUAL277EQUALReactome Database ID Release 71141646Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=141646ReactomeR-HSA-1416461Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-141646.11CASP3CASP3(29-175)Caspase-3 (large subunit)Reactome DB_ID: 14164429EQUAL175EQUALReactome Database ID Release 71141644Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=141644ReactomeR-HSA-1416441Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-141644.11Reactome Database ID Release 71350888Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=350888ReactomeR-HSA-3508883Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-350888.32Reactome Database ID Release 71350870Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=350870ReactomeR-HSA-3508703Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-350870.3XIAP:CASP3XIAP:Caspase-3Reactome DB_ID: 11430421Reactome Database ID Release 71114304Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=114304ReactomeR-HSA-1143043Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-114304.3Reactome Database ID Release 719627104Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9627104ReactomeR-HSA-96271042Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9627104.211230124Pubmed2001Recruitment, activation and retention of caspases-9 and -3 by Apaf-1 apoptosome and associated XIAP complexesBratton, S BWalker, GSrinivasula, S MSun, X MButterworth, MAlnemri, E SCohen, G MEMBO J. 20:998-100911257231Pubmed2001Structural basis of caspase inhibition by XIAP: differential roles of the linker versus the BIR domainHuang, YPark, YCRich, RLSegal, DMyszka, DGWu, HCell 104:781-9015650747Pubmed2005XIAP inhibits caspase-3 and -7 using two binding sites: evolutionarily conserved mechanism of IAPsScott, Fiona LDenault, JBRiedl, Stefan JShin, HwainRenatus, MartinSalvesen, Guy SEMBO J. 24:645-55INHIBITIONactiveUnit: #Protein4Reactome Database ID Release 719627383Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=962738311257232Pubmed2001Structural basis for the inhibition of caspase-3 by XIAPRiedl, S JRenatus, MSchwarzenbacher, RZhou, QSun, CFesik, S WLiddington, R CSalvesen, G SCell 104:791-800DIABLO:XIAP:Caspase-3Reactome DB_ID: 1143051SMAC dimerDIABLO dimerDIABLO:DIABLOReactome DB_ID: 9627054SMACDIABLOSmac protein, mitochondrial precursorSecond mitochondria-derived activator of caspaseDirect IAP binding protein with low pIReactome DB_ID: 114298UniProt:Q9NR28 DIABLODIABLOSMACFUNCTION Promotes apoptosis by activating caspases in the cytochrome c/Apaf-1/caspase-9 pathway. Acts by opposing the inhibitory activity of inhibitor of apoptosis proteins (IAP). Inhibits the activity of BIRC6/bruce by inhibiting its binding to caspases. Isoform 3 attenuates the stability and apoptosis-inhibiting activity of XIAP/BIRC4 by promoting XIAP/BIRC4 ubiquitination and degradation through the ubiquitin-proteasome pathway. Isoform 3 also disrupts XIAP/BIRC4 interacting with processed caspase-9 and promotes caspase-3 activation. Isoform 1 is defective in the capacity to down-regulate the XIAP/BIRC4 abundance.SUBUNIT Homodimer. Interacts with BEX3 (By similarity). Interacts with BIRC2/c-IAP1, BIRC3/c-IAP2, XIAP/BIRC4, BIRC6/bruce and BIRC7/livin. Interacts with the monomeric and dimeric form of BIRC5/survivin.TISSUE SPECIFICITY Ubiquitously expressed with highest expression in testis. Expression is also high in heart, liver, kidney, spleen, prostate and ovary. Low in brain, lung, thymus and peripheral blood leukocytes. Isoform 3 is ubiquitously expressed.DOMAIN The mature N-terminus mediates interaction with XIAP/BIRC4.PTM Ubiquitinated by BIRC7/livin.UniProtQ9NR2856EQUAL239EQUALReactome Database ID Release 71114298Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=114298ReactomeR-HSA-1142981Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-114298.12Reactome Database ID Release 719627054Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9627054ReactomeR-HSA-96270541Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9627054.11Reactome Database ID Release 71114305Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=114305ReactomeR-HSA-1143052Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-114305.2LEFT-TO-RIGHTXIAP binds CASP7The inhibitor‑of‑apoptosis (IAP) family of proteins such as X‑linked IAP (XIAP) suppress cell death by inhibiting the catalytic activity of caspases (Deveraux QL et al. 1997; Paulsen M et al. 2008). XIAP consists of three bacculoviral inhibitory repeat (BIR) domains and a C‑terminal ring finger. Biochemical and structural analyses revealed that the linker connecting BIR1 to BIR2 inhibits executioner caspase‑3 and ‑7 by positioning itself at the active site (Sun C et al. 1999; Riedl SJ et al. 2001; Huang Y et al. 2001; Chai J et al. 2001). Formation of a complex between caspase‑3 or caspase‑7 and the XIAP BIR2‑linker region appears to be driven by interactions between XIAP's Leu141 and Val146 and a hydrophobic site present on both caspases. This hydrophobic site is not found in caspase‑8 or caspase‑9, perhaps explaining the binding specificity of XIAP (Riedl SJ et al. 2001). BIR2 domain of XIAP may also contribute to inhibition of executioner caspases by interacting with additional sites on the enzymes (Scott FL et al. 2005; Abhari BA & Davoodi J 2008).Authored: Shamovsky, Veronica, 2017-07-26Reviewed: Matthews, Lisa, 2018-11-05Edited: Shamovsky, Veronica, 2018-11-02Caspase-72x(CASP7(24-198):CASP7(207-303))Reactome DB_ID: 141643caspase-7 heterodimerCASP7(24-198):CASP7(207-303)Reactome DB_ID: 6804359CASP7(24-198)Caspase-7 (large subunit)Caspase-7 subunit p20Reactome DB_ID: 141641UniProt:P55210 CASP7CASP7MCH3FUNCTION Involved in the activation cascade of caspases responsible for apoptosis execution. Cleaves and activates sterol regulatory element binding proteins (SREBPs). Proteolytically cleaves poly(ADP-ribose) polymerase (PARP) at a '216-Asp-|-Gly-217' bond. Overexpression promotes programmed cell death.ACTIVITY REGULATION Inhibited by isatin sulfonamides.SUBUNIT Heterotetramer that consists of two anti-parallel arranged heterodimers, each one formed by a 20 kDa (p20) and a 11 kDa (p11) subunit. Interacts with BIRC6/bruce. Interacts with ATXN3 (short isoform 1) (PubMed:30455355).TISSUE SPECIFICITY Highly expressed in lung, skeletal muscle, liver, kidney, spleen and heart, and moderately in testis. No expression in the brain.PTM Cleavages by granzyme B or caspase-10 generate the two active subunits. Propeptide domains can also be cleaved efficiently by caspase-3. Active heterodimers between the small subunit of caspase-7 and the large subunit of caspase-3, and vice versa, also occur.SIMILARITY Belongs to the peptidase C14A family.UniProtP5521024EQUAL198EQUALReactome Database ID Release 71141641Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=141641ReactomeR-HSA-1416412Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-141641.21CASP7(207-303)Caspase-7 (small subunit)Caspase-7 subunit p11Reactome DB_ID: 141642207EQUAL303EQUALReactome Database ID Release 71141642Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=141642ReactomeR-HSA-1416422Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-141642.21Reactome Database ID Release 716804359Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6804359ReactomeR-HSA-68043591Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6804359.12Reactome Database ID Release 71141643Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=141643ReactomeR-HSA-1416434Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-141643.42XIAP:Caspase-7Reactome DB_ID: 11430812Reactome Database ID Release 71114308Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=114308ReactomeR-HSA-1143082Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-114308.2Reactome Database ID Release 719627107Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9627107ReactomeR-HSA-96271072Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9627107.218521960Pubmed2008Interaction with XIAP prevents full caspase-3/-7 activation in proliferating human T lymphocytesPaulsen, MarenUssat, SandraJakob, MartenScherer, GudrunLepenies, IngaSchütze, StefanKabelitz, DieterAdam-Klages, SabineEur. J. Immunol. 38:1979-8711257230Pubmed2001Structural basis of caspase-7 inhibition by XIAPChai, JShiozaki, ESrinivasula, S MWu, QDatta, PAlnemri, E SShi, YDataa, PCell 104:769-80INHIBITIONReactome Database ID Release 719627076Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=962707610972280Pubmed2000Structural and biochemical basis of apoptotic activation by Smac/DIABLOChai, JDu, CWu, J WKyin, SWang, XShi, YNature 406:855-6211242052Pubmed2001A conserved XIAP-interaction motif in caspase-9 and Smac/DIABLO regulates caspase activity and apoptosisSrinivasula, S MHegde, RSaleh, ADatta, PShiozaki, EChai, JLee, R ARobbins, P DFernandes-Alnemri, TShi, YAlnemri, E SNature 410:112-6SMAC (DIABLO) binds to IAPs Second mitochondria‑derived activator of caspases protein (SMAC, also known as direct IAP binding protein with low pI or DIABLO) in its dimeric form interacts and antagonizes X‑linked inhibitor of apoptosis protein (XIAP) by concurrently targeting both BIR2 and BIR3 domains of XIAP (Chai J et al. 2000; Liu Z et sl. 2000; Burke SP & Smith JB 2010). XIAP inhibits apoptosis by binding to and inhibiting the effectors caspase‑3 and ‑7 and an initiator caspase‑9 (Deveraux QL et al. 1997; Paulsen M et al. 2008). During apoptosis, SMAC (DIABLO) is released from the mitochondria (Du C et al. 2000). In the cytosol, SMAC binds to XIAP displacing it from caspase:XIAP complexes liberating the active caspases (Wu G et al. 2000; Abhari BA & Davoodi J 2008).Reviewed: Matthews, Lisa, 2018-09-25Edited: Shamovsky, Veronica, 2018-11-07LEFT-TO-RIGHTSMAC (DIABLO) binds XIAPSecond mitochondria derived activator of caspase/direct inhibitor of apoptosis binding protein with low pI (SMAC, also known as DIABLO) is normally a mitochondrial protein but is released into the cytosol when cells undergo apoptosis (Du C et al. 2000). Mitochondrial import and cleavage of its signal peptide are required for SMAC to gain its apoptotic activity (Du C et al. 2000). In vitro studies revealed that dimerization was required for its function, while monomerization of cytosolic mature SMAC attenuated interaction with XIAP (Chai J et al. 2000; Burke SP & Smith JB 2010). Moreover, SMAC dimer showed high stability in vitro as measured by high hydrostatic pressure, low and high temperatures, and chemical denaturation (Goncalves RB et al. 2008). Binding of SMAC (DIABLO) to the BIR3 region of X linked inhibitor of apoptosis protein (XIAP) competitively inhibits binding of XIAP to caspase 9, while binding to the BIR2 region sterically hinders the interaction of XIAP with CASP3 and CASP7 (Srinivasula SM et al. 2001; Abhari BA & Davoodi J 2008).Authored: Shamovsky, Veronica, 2017-07-26Reviewed: Matthews, Lisa, 2018-11-05Edited: Shamovsky, Veronica, 2018-11-022DIABLO:XIAPDIABLO dimer:XIAPSMAC dimer:XIAPReactome DB_ID: 962739121Reactome Database ID Release 719627391Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9627391ReactomeR-HSA-96273911Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9627391.1Reactome Database ID Release 719627350Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9627350ReactomeR-HSA-96273501Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9627350.120957035Pubmed2010Monomerization of cytosolic mature smac attenuates interaction with IAPs and potentiation of caspase activationBurke, Stephen PSmith, Jeffrey BPLoS ONE 5:11140638Pubmed2000Structural basis of IAP recognition by Smac/DIABLOWu, GChai, JSuber, T LWu, J WDu, CWang, XShi, YNature 408:1008-1210929711Pubmed2000Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibitionDu, CFang, MLi, YLi, LWang, XCell 102:33-4218307314Pubmed2008The proapoptotic protein Smac/DIABLO dimer has the highest stability as measured by pressure and urea denaturationGonçalves, Rafael BSanches, DanielSouza, Theo L FSilva, Jerson LOliveira, Andréa CBiochemistry 47:3832-4118619610Pubmed2008A mechanistic insight into SMAC peptide interference with XIAP-Bir2 inhibition of executioner caspasesAbhari, Behnaz AhangarianDavoodi, JamshidJ. Mol. Biol. 381:645-54LEFT-TO-RIGHTSMAC binds XIAP:Caspase-3Binding of a dimeric SMAC (DIABLO) N‑terminal peptide with the BIR2 domain of XIAP effectively antagonizes inhibition of caspase‑3 by XIAP (Wu G et al. 2000; Chai J et al. 2000). SMAC (DIABLO) interacts with the BIR3 and then BIR2 domains of XIAP sequentially, and such dynamic interaction cooperatively neutralizes inhibition of caspase‑3 by the linker region of XIAP (Gao Z et al. 2007). Reviewed: Matthews, Lisa, 2018-11-05Edited: Shamovsky, Veronica, 2018-11-07Reactome Database ID Release 71114306Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=114306ReactomeR-HSA-1143063Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-114306.317724022Pubmed2007A dimeric Smac/diablo peptide directly relieves caspase-3 inhibition by XIAP. Dynamic and cooperative regulation of XIAP by Smac/DiabloGao, ZhonghuaTian, YuanWang, JunruYin, QWu, HLi, Yue-MingJiang, XuejunJ. Biol. Chem. 282:30718-279230442Pubmed1997X-linked IAP is a direct inhibitor of cell-death proteases.Deveraux, QLTakahashi, RSalvesen, Guy S.Reed, JCNature 388:300-414960576Pubmed2004Smac/DIABLO selectively reduces the levels of c-IAP1 and c-IAP2 but not that of XIAP and livin in HeLa cells.Yang, QHDu, CJ Biol Chem 279:16963-70LEFT-TO-RIGHTSMAC binds XIAP:Caspase-7The linker region preceding BIR2 of XIAP is responsible for the inhibition of caspase‑3 and ‑7, which is further stabilized by interaction with the BIR2 domain itself (Scott et al. 2005). Binding of a dimeric SMAC (DIABLO) N‑terminal peptide with the BIR2 domain of XIAP effectively antagonized inhibition of caspase‑7 by XIAP (Wu G et al. 2000; Chai J et al. 2000). Reviewed: Matthews, Lisa, 2018-11-05Edited: Shamovsky, Veronica, 2018-11-07SMAC:XIAP:Caspase-7DIABLO:XIAP:Caspase-7Reactome DB_ID: 11435311Reactome Database ID Release 71114353Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=114353ReactomeR-HSA-1143532Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-114353.2Reactome Database ID Release 71114354Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=114354ReactomeR-HSA-1143544Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-114354.4LEFT-TO-RIGHTSMAC binds XIAP within apoptosomeX linked inhibitor of apoptosis protein (XIAP) associates with the active caspase 9 (CASP9) within the APAF1 apoptosome complex. XIAP consists of three baculoviral IAP repeat (BIR) domains and a COOH terminal RING domain (Duckett CS et al. 1996). The BIR3 region of XIAP binds to the amino terminus of the linker peptide on the small subunit of CASP9, which becomes exposed after proteolytic processing of procaspase 9 at Asp315 (Srinivasula SM et al. 2001). SMAC (DIABLO) competes with CASP9 for binding to BIR3 domain of XIAP promoting the release of XIAP from the CASP9:apoptosome complex (Du et al. 2000; Liu Z et al. 2000; Srinivasula SM et al. 2001).Reviewed: Matthews, Lisa, 2018-11-05Edited: Shamovsky, Veronica, 2018-11-07XIAP:apoptosomeXIAP:APAF1:CYCS:CASP9Reactome DB_ID: 96270662ApoptosomeCYCSC:APAF1:CASP9Reactome DB_ID: 114258APAF1:CYCSAPAF1:Cytochrome CReactome DB_ID: 114253APAF1Apaf-1Apoptotic protease activating factor 1Reactome DB_ID: 50099UniProt:O14727 APAF1APAF1KIAA0413FUNCTION Oligomeric Apaf-1 mediates the cytochrome c-dependent autocatalytic activation of pro-caspase-9 (Apaf-3), leading to the activation of caspase-3 and apoptosis. This activation requires ATP. Isoform 6 is less effective in inducing apoptosis.SUBUNIT Monomer. Oligomerizes to a heptameric ring, known as the apoptosome, upon binding of cytochrome c and dATP. Oligomeric Apaf-1 and pro-caspase-9 bind to each other via their respective NH2-terminal CARD domains and consecutively mature caspase-9 is released from the complex. Pro-caspase-3 is recruited into the Apaf-1-pro-caspase-9 complex via interaction with pro-caspase-9. Interacts with APIP. Interacts (via CARD and NACHT domains) with NAIP/BIRC1 (via NACHT domain). Interacts with CIAO2A (PubMed:25716227).TISSUE SPECIFICITY Ubiquitous. Highest levels of expression in adult spleen and peripheral blood leukocytes, and in fetal brain, kidney and lung. Isoform 1 is expressed in heart, kidney and liver.INDUCTION By E2F and p53/TP53 in apoptotic neurons.DOMAIN The CARD domain mediates interaction with APIP.DOMAIN The monomeric form is autoinhibited in a closed conformation through a bound ADP at the nucleotide binding site. Exchange of ADP for ATP and binding of cytochrome c trigger a large conformational change where the first WD repeat region swings out, allowing the NB-ARC domain to rotate and expose the contact areas for oligomerization (By similarity).MISCELLANEOUS Physiological concentrations of calcium ions negatively affect the assembly of apoptosome by inhibiting nucleotide exchange in the monomeric form.UniProtO147271EQUAL1248EQUALReactome Database ID Release 7150099Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=50099ReactomeR-HSA-500991Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-50099.11CYCSCytochrome cReactome DB_ID: 53259UniProt:P99999 CYCSCYCSCYCFUNCTION Electron carrier protein. The oxidized form of the cytochrome c heme group can accept an electron from the heme group of the cytochrome c1 subunit of cytochrome reductase. Cytochrome c then transfers this electron to the cytochrome oxidase complex, the final protein carrier in the mitochondrial electron-transport chain.FUNCTION Plays a role in apoptosis. Suppression of the anti-apoptotic members or activation of the pro-apoptotic members of the Bcl-2 family leads to altered mitochondrial membrane permeability resulting in release of cytochrome c into the cytosol. Binding of cytochrome c to Apaf-1 triggers the activation of caspase-9, which then accelerates apoptosis by activating other caspases.PTM Binds 1 heme group per subunit.PTM Phosphorylation at Tyr-49 and Tyr-98 both reduce by half the turnover in the reaction with cytochrome c oxidase, down-regulating mitochondrial respiration.SIMILARITY Belongs to the cytochrome c family.UniProtP999992EQUAL105EQUALReactome Database ID Release 7153259Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=53259ReactomeR-HSA-532591Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-53259.11Reactome Database ID Release 71114253Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=114253ReactomeR-HSA-1142532Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-114253.27Cleaved Caspase-9Reactome DB_ID: 141640CASP9 p35CASP9(?-315)Caspase-9 subunit p35Caspase-9 (large subunit)Reactome DB_ID: 141638UniProt:P55211 CASP9CASP9MCH6FUNCTION Involved in the activation cascade of caspases responsible for apoptosis execution. Binding of caspase-9 to Apaf-1 leads to activation of the protease which then cleaves and activates caspase-3. Promotes DNA damage-induced apoptosis in a ABL1/c-Abl-dependent manner. Proteolytically cleaves poly(ADP-ribose) polymerase (PARP).FUNCTION Isoform 2 lacks activity is an dominant-negative inhibitor of caspase-9.ACTIVITY REGULATION Inhibited by the effector protein NleF that is produced by pathogenic E.coli; this inhibits apoptosis.SUBUNIT Heterotetramer that consists of two anti-parallel arranged heterodimers, each one formed by a 35 kDa (p35) and a 10 kDa (p10) subunit. Caspase-9 and APAF1 bind to each other via their respective NH2-terminal CED-3 homologous domains in the presence of cytochrome C and ATP. Interacts (inactive form) with EFHD2. Interacts with HAX1. Interacts with BIRC2/c-IAP1, XIAP/BIRC4, BIRC5/survivin, BIRC6/bruce and BIRC7/livin. Interacts with ABL1 (via SH3 domain); the interaction is direct and increases in the response of cells to genotoxic stress and ABL1/c-Abl activation. Interacts with NleF from pathogenic E.coli.TISSUE SPECIFICITY Ubiquitous, with highest expression in the heart, moderate expression in liver, skeletal muscle, and pancreas. Low levels in all other tissues. Within the heart, specifically expressed in myocytes.DEVELOPMENTAL STAGE Expressed at low levels in fetal heart, at moderate levels in neonate heart, and at high levels in adult heart.PTM Cleavages at Asp-315 by granzyme B and at Asp-330 by caspase-3 generate the two active subunits. Caspase-8 and -10 can also be involved in these processing events.PTM Phosphorylated at Thr-125 by MAPK1/ERK2. Phosphorylation at Thr-125 is sufficient to block caspase-9 processing and subsequent caspase-3 activation. Phosphorylation on Tyr-153 by ABL1/c-Abl; occurs in the response of cells to DNA damage.SIMILARITY Belongs to the peptidase C14A family.UniProtP552111EQUAL315EQUALReactome Database ID Release 71141638Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=141638ReactomeR-HSA-1416381Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-141638.11CASP9CASP9(331-416)CASP9 p10Caspase-9 (small subunit)Caspase-9 subunit p10Reactome DB_ID: 141639331EQUAL416EQUALReactome Database ID Release 71141639Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=141639ReactomeR-HSA-1416392Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-141639.21Reactome Database ID Release 71141640Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=141640ReactomeR-HSA-1416401Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-141640.12Reactome Database ID Release 71114258Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=114258ReactomeR-HSA-1142582Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-114258.21Reactome Database ID Release 719627066Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9627066ReactomeR-HSA-96270661Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9627066.1APAF1:CYCS:CASP9:XIAP:SMACAPAF1:CYCS:CASP9:XIAP:DIABLOReactome DB_ID: 11431811Reactome Database ID Release 71114318Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=114318ReactomeR-HSA-1143182Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-114318.2Reactome Database ID Release 71114361Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=114361ReactomeR-HSA-1143613Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-114361.38654366Pubmed1996A conserved family of cellular genes related to the baculovirus iap gene and encoding apoptosis inhibitorsDuckett, C SNava, V EGedrich, R WClem, R JVan Dongen, J LGilfillan, M CShiels, HHardwick, J MThompson, C BEMBO J. 15:2685-9411140637Pubmed2000Structural basis for binding of Smac/DIABLO to the XIAP BIR3 domainLiu, ZSun, COlejniczak, E TMeadows, R PBetz, S FOost, THerrmann, JWu, J CFesik, S WNature 408:1004-811084335Pubmed2000ML-IAP, a novel inhibitor of apoptosis that is preferentially expressed in human melanomas.Vucic, DStennicke, HRPisabarro, MTSalvesen, Guy S.Dixit, VMCurr Biol 10:1359-66Reactome Database ID Release 71111463Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=111463ReactomeR-HSA-1114633Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-111463.312042762Pubmed2002IAP proteins: blocking the road to death's doorSalvesen, Guy S.Duckett, CSNat Rev Mol Cell Biol 3:401-10SMAC(DIABLO)-mediated dissociation of IAP:caspase complexes Second mitochondria derived activator of caspase/direct inhibitor of apoptosis binding protein with low pI (SMAC, also known as DIABLO) regulates XIAP function and potentiates caspase-3, -7 and -9 activity by disrupting the interaction of caspases with XIAP. Residues 56-59 of SMAC (DIABLO) are homologous to the amino-terminal motif that is used by caspase-9 (CASP9) to bind to the BIR3 domain of XIAP. SMAC (DIABLO) competes with CASP9 for binding to BIR3 domain of XIAP promoting the release of XIAP from the CASP9:apoptosome complex (Srinivasula SM et al. 2001; Salvesen et al. 2002). The binding of SMAC to the BIR2 and BIR3 regions of XIAP creates a steric hindrance that is essential for preventing binding of XIAP linker region with effector caspases CASP3 and CASP7 thus achieving neutralization of XIAP inhibition. The strong affinity for XIAP allows SMAC (DIABLO) to displace caspase-3, -7 from the XIAP:caspase complexes (Wu G et al. 2000; Chai J et al. 2001; Huang Y et al. 2003; Abhari BA & Davoodi J 2008).Reviewed: Matthews, Lisa, 2018-03-02Edited: Shamovsky, Veronica, 2018-11-02LEFT-TO-RIGHTDissociation of Caspase-3 from DIABLO:XIAP:Caspase-3The linker region preceding BIR2 of XIAP is responsible for the inhibition of caspase-3 and -7, which is further stabilized by interaction with the BIR2 domain itself (Scott et al. 2005). Binding of DIABLO (SMAC) to BIR2 domain of XIAP can destabillize the XIAP:CASP3 interaction promoting the liberation of active caspase-3 from its complex with XIAP (Kashkar et al. 2003). Furthermore, SMAC (DIABLO) interacted with the BIR3 and then BIR2 domains of XIAP sequentially, and such dynamic interaction cooperatively neutralized inhibition of caspase-3 by the linker region of XIAP (Gao Z et al. 2007). Authored: Alnemri, E, 2004-02-17 00:23:30Reviewed: Matthews, Lisa, 2018-11-05Edited: Shamovsky, Veronica, 2018-11-02Reactome Database ID Release 71114419Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=114419ReactomeR-HSA-1144194Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-114419.412874265Pubmed2003XIAP-mediated caspase inhibition in Hodgkin's lymphoma-derived B cellsKashkar, HamidHaefs, ChristianeShin, HwainHamilton-Dutoit, Stephen JSalvesen, Guy SKronke, MartinJurgensmeier, Juliane MJ. Exp. Med. 198:341-7LEFT-TO-RIGHTDissociation of Caspase-7 from DIABLO:XIAP:Caspase-7The linker region preceding BIR2 of XIAP is responsible for the inhibition of caspase-3 and -7, which is further stabilized by interaction with the BIR2 domain itself (Scott et al. 2005). Binding of a dimeric SMAC (DIABLO) N-terminal peptide with the BIR2 domain of XIAP effectively antagonized inhibition of caspase-7 by XIAP (Wu G et al. 2000; Chai J et al. 2000). As DIABLO has a higher affinity for the BIR2 domain than caspase-7, DIABLO (SMAC) binding to XIAP results in the liberation of caspase-7 (Huang et al. 2001).Authored: Alnemri, E, 2004-02-17 00:23:30Reviewed: Matthews, Lisa, 2018-11-05Edited: Shamovsky, Veronica, 2018-11-02Reactome Database ID Release 71114392Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=114392ReactomeR-HSA-1143923Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-114392.3LEFT-TO-RIGHTDissociation of DIABLO:XIAP from the apoptosome complexX linked inhibitor of apoptosis protein (XIAP) associates with the active caspase 9 (CASP9) within APAF1 apoptosome complex. Binding of DIABLO (SMAC) to XIAP promotes the release of caspase-9 from XIAP (Du et al. 2000). XIAP consists of three baculoviral IAP repeat (BIR) domains and a COOH terminal RING domain (Duckett CS et al. 1996). The BIR3 region binds to the amino terminus of the linker peptide on the small subunit of CASP9, which becomes exposed after proteolytic processing of procaspase 9 at Asp315 (Srinivasula SM et al. 2001). SMAC (DIABLO) competes with CASP9 for binding to BIR3 domain of XIAP promoting the release of XIAP from the CASP9:apoptosome complex (Du et al. 2000; Srinivasula SM et al. 2001).Authored: Alnemri, E, 2004-02-17 00:23:30Reviewed: Matthews, Lisa, 2018-11-05Edited: Shamovsky, Veronica, 2018-11-02Reactome Database ID Release 71114440Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=114440ReactomeR-HSA-1144403Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-114440.3Reactome Database ID Release 71111464Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=111464ReactomeR-HSA-1114643Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-111464.314512414Pubmed2003Requirement of both the second and third BIR domains for the relief of X-linked inhibitor of apoptosis protein (XIAP)-mediated caspase inhibition by SmacHuang, YihuaRich, RLMyszka, David GWu, HJ. Biol. Chem. 278:49517-22LEFT-TO-RIGHTSEPT4 binds XIAPSEPT4 (known also as ARTS, an apoptosis-related protein in the TGF-beta signaling pathway) is a pro-apoptotic mitochondrial protein (Gottfried Y et al. 2004). SEPT4 is an unique member of the septin family which functions as a tumor suppressor. SEPT4 promotes apoptosis through binding and antagonizing inhibitor of apoptosis (IAP) proteins and specifically X linked IAP (XIAP) (Gottfried Y et al. 2004). NMR and fluorescence spectroscopy showed that the C-terminal domain (CTD) of SEPT4 directly binds BIR3 domain of XIAP. The BIR3 interacting region in SEPT4 CTD was mapped to SEPT4 residues 266 - 274, which are the nine C-terminal residues in the protein (Bornstein B et al. 2011; Reingewertz TH et al. 2011).Authored: Shamovsky, Veronica, 2017-07-26Reviewed: Matthews, Lisa, 2018-11-05Edited: Shamovsky, Veronica, 2018-11-02SEPT4 dimerReactome DB_ID: 9627347ARTSSEPT4SEPT4_i2Reactome DB_ID: 6805825UniProt:O43236-6 SEPTIN4SEPTIN4ARTSPNUTL2SEP4SEPT4hucep-7FUNCTION Filament-forming cytoskeletal GTPase (By similarity). May play a role in cytokinesis (Potential). Forms a filamentous structure with SEPTIN12, SEPTIN6, SEPTIN2 and probably SEPTIN4 at the sperm annulus which is required for the structural integrity and motility of the sperm tail during postmeiotic differentiation (PubMed:25588830). May play a role in platelet secretion. Isoform ARTS, but not the other isoforms, is required for the induction of cell death mediated by TGF-beta and by other apoptotic stimuli.SUBUNIT Septins polymerize into heterooligomeric protein complexes that form filaments, and can associate with cellular membranes, actin filaments and microtubules. GTPase activity is required for filament formation (By similarity). Interacts with SEPTIN8. In a mesenchymal cell line, interacts with SEPTIN9 isoform 2 variants HNA Trp-106 and Phe-111, but not the wild type SEPTIN9. Component of a septin core octomeric complex consisting of SEPTIN12, SEPTIN7, SEPTIN6 and SEPTIN2 or SEPTIN4 in the order 12-7-6-2-2-6-7-12 or 12-7-6-4-4-6-7-12 and located in the sperm annulus. Isoform ARTS, but no other isoforms, interacts with XIAP after the induction of apoptosis.TISSUE SPECIFICITY Widely expressed in adult and fetal tissues with highest expression in adult brain (at protein level), heart, liver and adrenal gland and fetal heart, kidney, liver and lung. Also expressed in colorectal cancers and malignant melanomas. Expressed in platelets.SIMILARITY Belongs to the TRAFAC class TrmE-Era-EngA-EngB-Septin-like GTPase superfamily. Septin GTPase family.UniProt IsoformO43236-61EQUAL274EQUALReactome Database ID Release 716805825Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6805825ReactomeR-HSA-68058251Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6805825.12Reactome Database ID Release 719627347Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9627347ReactomeR-HSA-96273471Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9627347.1SEPT4 dimer:XIAPReactome DB_ID: 962744121Reactome Database ID Release 719627441Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9627441ReactomeR-HSA-96274411Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9627441.1Reactome Database ID Release 719627369Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9627369ReactomeR-HSA-96273691Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9627369.121695558Pubmed2011ARTS binds to a distinct domain in XIAP-BIR3 and promotes apoptosis by a mechanism that is different from other IAP-antagonistsBornstein, BavatGottfried, YossiEdison, NataliaShekhtman, AnnaLev, TaliGlaser, FabianLarisch, SaritApoptosis 16:869-8115029247Pubmed2004The mitochondrial ARTS protein promotes apoptosis through targeting XIAPGottfried, YossiRotem, AsafLotan, RonaSteller, HermannLarisch, SaritEMBO J. 23:1627-3521949740Pubmed2011Mechanism of the interaction between the intrinsically disordered C-terminus of the pro-apoptotic ARTS protein and the Bir3 domain of XIAPReingewertz, Tali HShalev, Deborah ESukenik, ShaharBlatt, OfrahRotem-Bamberger, ShaharLebendiker, MarioLarisch, SaritFriedler, AssafPLoS ONE 6:e24655Reactome Database ID Release 71111469Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=111469ReactomeR-HSA-1114693Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-111469.315077149Pubmed2004Toxic proteins released from mitochondria in cell deathSaelens, XFestjens, NVande Walle, Lvan Gurp, Mvan Loo, GVandenabeele, POncogene 23:2861-74