Search results for UCHL3

Showing 16 results out of 16

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Protein (1 results from a total of 1)

Identifier: R-HSA-5690773
Species: Homo sapiens
Compartment: cytosol
Primary external reference: UniProt: UCHL3: P15374

Reaction (5 results from a total of 5)

Identifier: R-HSA-5690319
Species: Homo sapiens
Compartment: cytosol
UCHL1 and UCHL3 can hydrolyze several short C-terminal ubiquitin adducts to generate ubiquitin monomers (Wilkinson et al. 1989, Wada et al. 1998, Larsen et al. 1998). This liberates small molecule nucleophiles that may have inadvertently reacted with Ub C-terminal thiolesters. Because these enzymes can cleave small peptides from the C-terminus of Ub, they could also function in recycling Ub from incomplete proteasomal or lysosomal protein degradation. UCHL3, but not UCHL1, is able to cleave the C-terminus of Neural precursor cell expressed developmentally downregulated protein 8 (NEDD8), a ubiquitin-like protein that activates the largest ubiquitin E3 ligase family, the cullin-RING ligases (Wada et al. 1998, Enchev et al. 2015). UCHL1 and 3 are specifically expressed in neurons, cells of the diffuse neuroendocrine system and their tumors. A polymorphism (S18Y) in UCHL1 is associated with a reduced risk for Parkinson's disease (Wang et al. 2002) and its overexpression is protective in models of Alzheimer's disease (Gong et al. 2006). UCHL1 has been shown to interact with alpha-synuclein, but as a ubiquitin ligase rather than as a ubiquitin hydrolase (Liu et al. 2002). It is K63-polyubiquitinated by Parkin in cooperation with the Ubc13/Uev1a E2 ubiquitin-conjugating enzyme complex, promoting UCH-L1 degradation by the autophagy-lysosome pathway (McKeon et al. 2015).
Identifier: R-HSA-5690808
Species: Homo sapiens
Compartment: cytosol
UCHL3 and SENP8 (DEN1) remove the C-terminal extension of NEDD8 propeptides, exposing a C-terminal Gly residue. UCHL3 can also process ubiquitin (Wada et al. 1998). UCHL3 and SENP8 are probably functionally redundant in NEDD8 processing as deletion of either enzyme does not lead to neddylation defects (Chan et al. 2008, Kurihara et al. 2000).
Identifier: R-HSA-8853514
Species: Homo sapiens
Compartment: cytosol
The UBA52 precursor protein contains the ribosomal protein L40 and ubiquitin (UBA52 residues 1 to 76) which are released by proteolysis. Any of the proteases UCHL3, USP7, or USP9X can catalyze the proteolysis reaction (Larsen et al. 1998, Grou et al. 2015).
Identifier: R-HSA-8853503
Species: Homo sapiens
Compartment: cytosol
The RPS27A precursor protein contains the ribosomal protein L40 and ubiquitin (RPS27A residues 1 to 76) which are released by proteolysis. Any of the proteases UCHL3, USP7, or USP9X can catalyze the proteolysis reaction (Larsen et al. 1998, Grou et al. 2015).
Identifier: R-HSA-8951644
Species: Homo sapiens
Compartment: cytosol
After C-terminal processing by UCHL3 or SENP8, mature NEDD8 is released (Wada et al, 1998; Wu et al, 2003).

Set (3 results from a total of 3)

Identifier: R-HSA-5690783
Species: Homo sapiens
Compartment: cytosol
Identifier: R-HSA-5690768
Species: Homo sapiens
Compartment: cytosol
Identifier: R-HSA-8853523
Species: Homo sapiens
Compartment: cytosol

Complex (4 results from a total of 4)

Identifier: R-HSA-6782592
Species: Homo sapiens
Compartment: cytosol
Identifier: R-HSA-6782643
Species: Homo sapiens
Compartment: cytosol
Identifier: R-HSA-6782635
Species: Homo sapiens
Compartment: cytosol
Identifier: R-HSA-6782633
Species: Homo sapiens
Compartment: cytosol

Pathway (3 results from a total of 3)

Identifier: R-HSA-8866652
Species: Homo sapiens
Ubiquitin monomers are processed from larger precursors and then activated by formation of a thiol ester bond between ubiquitin and a cysteine residue of an E1 activating enzyme (UBA1 or UBA6, Jin et al. 2007). The ubiquitin is then transferred to the active site cysteine residue of an E2 conjugating enzyme (reviewed in van Wijk and Timmers 2010, Kleiger and Mayor 2014, Stewart et al. 2016). Precursor proteins containing multiple ubiquitin monomers (polyubiquitins) are produced from the UBB and UBC genes. Precursors containing a single ubiquitin fused to a ribosomal protein are produced from the UBA52 and RPS27A genes. The proteases OTULIN and USP5 are very active in polyubiquitin processing, whereas the proteases UCHL3, USP7, and USP9X cleave the ubiquitin-ribosomal protein precursors yielding ubiquitin monomers (Grou et al. 2015). Other enzymes may also process ubiquitin precursors. A resultant ubiquitin monomer is activated by adenylation of its C-terminal glycine followed by conjugation of the C-terminus to a cysteine residue of the E1 enzymes UBA1 or UBA6 via a thiol ester bond (Jin et al. 2007, inferred from rabbit homologues in Haas et al. 1982, Hershko et al. 1983). The ubiquitin is then transferred from the E1 enzyme to a cysteine residue of one of several E2 enzymes (reviewed in van Wijk and Timmers 2010, Stewart et al. 2016).
Identifier: R-HSA-8852135
Species: Homo sapiens
Ubiquitin is a small, 76 amino acid residue protein that is conjugated by E3 ubiquitin ligases to other proteins in order to regulate their function or degradation (enzymatic cascade reviewed in Neutzner and Neutzner 2012, Kleiger and Mayor 2014, structures and mechanisms of conjugating enzymes reviewed in Lorenz et al. 2013). Ubiquitination of target proteins usually occurs between the C-terminal glycine residue of ubiquitin and a lysine residue of the target, although linkages with cysteine, serine, and threonine residues are also observed (reviewed in Wang et al. 2012, McDowell and Philpott 2013).
Ubiquitin must first be processed from larger precursors and then activated by formation of a thiol ester bond between ubiquitin and an E1 activating enzyme (UBA1 or UBA6) and transfer to an E2 conjugating enzyme before being transferred by an E3 ligase to a target protein. Precursor proteins containing multiple ubiquitin monomers (polyubiquitins) are produced from the UBB and UBC genes; precursors containing a single ubiquitin monomer and a ribosomal protein are produced from the UBA52 and RPS27A genes. Many proteases (deubiquitinases) may potentially process these precursors yielding monomeric ubiquitin. The proteases OTULIN and USP5 are particularly active in cleaving the polyubiquitin precursors, whereas the proteases UCHL3, USP7, and USP9X cleave the ubiquitin-ribosomal protein precursors yielding ubiquitin monomers (Grou et al. 2015). A resultant ubiquitin monomer is activated by adenylation of the C-terminal glycine followed by conjugation of the C-terminus to a cysteine residue of the E1 enzymes UBA1 or UBA6 via a thiol ester bond. The ubiquitin is then transferred from the E1 enzyme to a cysteine residue of one of several E2 enzymes (reviewed in van Wijk and Timmers 2010, Stewart et al. 2016). Through a less well characterized mechanism, E3 ubiquitin ligases then bring a target protein and the E2-ubiquitin conjugate into proximity so that the ubiquitin is transferred via formation of an amide bond to a particular lysine residue (or, in rarer cases, a thiol ester bond to a cysteine residue or an ester bond to a serine or threonine residue) of the target protein (reviewed in Berndsen and Wolberger 2014). Based on protein homologies, families of E3 ubiquitin ligases have been identified that include RING-type ligases (reviewed in Deshaies et al. 2009, Metzger et al. 2012, Metzger et al. 2014), HECT-type ligases (reviewed in Rotin et al. 2009, Metzger et al. 2012), and RBR-type ligases (reviewed in Dove et al. 2016). A subset of the RING-type ligases participate in CULLIN-RING ligase complexes (CRLs which include SCF complexes, reviewed in Lee and Zhou 2007, Genschik et al. 2013, Skaar et al. 2013, Lee et al. 2014).
Some E3-E2 combinations catalyze mono-ubiquitination of the target protein (reviewed in Nakagawa and Nakayama 2015). Other E3-E2 combinations catalyze conjugation of further ubiquitin monomers to the initial ubiquitin, forming polyubiquitin chains. (It may also be possible for some E3-E2 combinations to preassemble polyubiquitin and transfer it as a unit to the target protein.) Ubiquitin contains several lysine (K) residues and a free alpha amino group to which further ubiquitin can be conjugated. Thus different types of polyubiquitin are possible: K11 linked polyubiquitin is observed in endoplasmic reticulum-associated degradation (ERAD), K29 linked polyubiquitin is observed in lysosomal degradation, K48 linked polyubiquitin directs target proteins to the proteasome for degradation, whereas K63 linked polyubiquitin generally acts as a scaffold to recruit other proteins in several cellular processes, notably DNA repair (reviewed in Komander et al. 2009). Ubiquitination is highly regulated (reviewed in Vittal et al. 2015) and affects all cellular processes including DNA damage response (reviewed in Brown and Jackson 2015), immune signaling (reviewed in Park et al. 2014, Lutz-Nicoladoni et al. 2015), and regulation of normal and cancerous cell growth (reviewed in Skaar and Pagano 2009, Yerlikaya and Yontem 2013, Strikoudis et al. 2014).
Identifier: R-HSA-8951664
Species: Homo sapiens
NEDD8 is a small ubiquitin-like molecule that is conjugated to substrate proteins through an E1 to E3 enzyme cascade similar to that for ubiquitin. The best characterized target of neddylation is the cullin scaffold subunit of cullin-RING E3 ubiquitin ligases (CRLs), which themselves target numerous cellular proteins for degradation by the proteasome (Hori et al, 1999; reviewed in Soucy et al, 2010; Lyedeard et al, 2013). The multisubunit CRL complexes are compositionally diverse, but each contains a scaffolding cullin protein (CUL1, 2, 3, 4A, 4B, 5, 7 or 9) and a RING box-containing E3 ligase subunit RBX, along with other adaptor and substrate-interacting subunits. RBX2 (also known as RNF7) interacts preferentially with CUL5, while RBX1 is the primary E3 for most other cullin family members (reviewed in Mahon et al, 2014). Neddylation of the cullin subunit increases the ubiquitination activity of the CRL complex (Podust et al, 2000; Read et al, 2000; Wu et al, 2000; Kawakami et al, 2001; Ohh et al, 2002; Yu et al, 2015). In addition to CRL complexes, a number of other less-well characterized NEDD8 targets have been identified. These include other E3 ubiquitin ligases such as SMURF1 and MDM2, receptor tyrosine kinases such as EGFR and TGF beta RII, and proteins that contribute to transcriptional regulation, among others (Xie et al, 2014; Watson et al, 2010; Oved et al, 2006; Zuo et al, 2013; Xirodimas et al, 2004; Singh et al, 2007; Abida et al, 2007; Liu et al 2010; Watson et al, 2006; Loftus et al, 2012; Aoki et al, 2013; reviewed in Enchev et al, 2015).
Like ubiquitin, NEDD8 undergoes post-translational processing to generate the mature form. UCHL3- or SENP8-mediated proteolysis removes the C-terminal 5 amino acids of NEDD8, generating a novel C-terminal glycine residue for conjugation to the cysteine residues in the E1, E2 enzymes or lysine residues in the substrate protein, usually the E3 NEDD8 ligase itself (Wada et al, 1998; reviewed in Enchev et al, 2015). Most substrates in vivo appear to be singly neddylated on one or more lysine residues, but NEDD8 chains have been formed on cullin substrates in vitro and on histone H4 in cultured human cells after DNA damage (Jones et al, 2008; Ohki et al, 2009; Xirodimas et al, 2008; Jeram et al, 2010; Ma et al, 2013; reviewed in Enchev et al, 2015). The significance of NEDD8 chains is still not clear.
NEDD8 has a single heterodimeric E1 enzyme, consisting of NAE1 (also known as APPBP1) and UBA3, and two E2 enzymes, UBE2M and UBE2F, which are N-terminally acetylated (Walden et al, 2003; Bohnsack et al, 2003; Huang et al, 2004; Huang et al, 2005; Huang et al, 2009; Scott et al, 2011a; Monda et al, 2013; reviewed in Enchev et al, 2015). All NEDD8 E3 enzymes reported to date also function as E3 ubiquitin ligases, and most belong to the RING domain class. The best characterized NEDD8 E3 enzymes are the CRL complexes described above. RBX1-containing complexes interact preferentially with UBE2M, while UBE2F is the E2 for RBX2-containing complexes (Huang et al, 2009; Monda et al, 2013).
Neddylation is regulated in vivo by interaction with DCUN1D proteins (also called DCNLs). The 5 human DCUN1D proteins interact both with cullins and with the NEDD8 E2 proteins and thereby increase the kinetic efficiency of neddylation (Kurz et al, 2005; Kurz et al, 2008; Scott et al, 2010; Scott et al, 2011a; Scott et al, 2014; Monda et al, 2013). Glomulin (GLMN) is another regulator of CRL function that binds to the neddylated cullin and competitively inhibits interaction with the ubiquitin E2 enzyme (Arai et al, 2003; Tron et al, 2012; Duda et al, 2012; reviewed in Mahon et al, 2014).
The multisubunit COP9 signalosome is the only cullin deneddylase, while SENP8 (also known as DEN1) contributes to deneddylation of other non-cullin NEDD8 targets (Cope et al, 2002; Emberley et al, 2012; Chan et al, 2008; Wu et al, 2003; reviewed in Wei et al, 2008; Enchev et al, 2015). In the deneddylated state, cullins bind to CAND1 (cullin associated NEDD8-dissociated protein1), which displaces the COP9 signalosome and promotes the exchange of the ubiquitin substrate-specific adaptor. This allows CRL complexes to be reconfigured to target other subtrates for ubiquitination (Liu et al, 2002; Schmidt et al, 2009; Pierce et al, 2013; reviewed in Mahon et al, 2014).

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