- Deubiquitinating enzyme
Deubiquitinating enzymes (DUBs) are a large group of proteases (more than 60 known) that regulate ubiquitin-dependent metabolic pathways by cleaving ubiquitin-protein bonds. DUBs are also commonly referred to as deubiquitinating peptidases, deubiquitinating isopeptidases, deubiquitinases, ubiquitin proteases, ubiquitin hydrolyases, ubiquitin isopeptidases, or DUbs. The human genome encodes nearly 100 DUBs with specificity for ubiquitin in five gene families. Potentially, DUBs may act as negative and positive regulators of the ubiquitin system. In addition to ubiquitin recycling, they are involved in processing of ubiquitin precursors, in proofreading of protein ubiquitination and in disassembly of inhibitory ubiquitin chains.
They may be associated with disease.
DUBs can be classified into two main classes: cysteine proteases and metalloproteases.
There are four main superfamilies of cysteine protease DUBs:
- the ubiquitin-specific processing protease (USP/UBP) superfamily; (USP1, USP2, USP3, USP4, USP5, USP6, USP7, USP8, USP9X, USP9Y, USP10, USP11, USP12, USP13, USP14, USP15, USP16, USP17, USP17L2, USP17L3, USP17L4, USP17L5, USP17L7, USP17L8, USP18, USP19, USP20, USP21, USP22, USP23, USP24, USP25, USP26, USP27X, USP28, USP29, USP30, USP31, USP32, USP33, USP34, USP35, USP36, USP37, USP38, USP39, USP40, USP41, USP42, USP43, USP44, USP45, USP46)
- the ubiquitin C-terminal hydrolyase (UCH) superfamily; (UCHH2, UCHL1, UCHL3)
- the ovarian tumour (OTU) superfamily;
- and the Machado-Josephin domain (MJD) superfamily. (OTUB1, OTUB2, ATXN3, ATXN3L)
However, there is also a little known putative group of DUBs called the permutated papain fold peptidases of dsDNA viruses and eukaryote (PPPDEs) superfamily, which, if shown to be bona fide DUBs, would be the fifth in the cysteine protease class.
The Jab1/Mov34/Mpr1 Pad1 N-terminal+ (MPN+) (JAMM) domain superfamily proteins bind zinc and hence are metalloproteases.
Role in the ubiquitin pathway
DUBs play several roles in the ubiquitin pathway. First, DUBs carry out activation of the ubiquitin proproteins, probably cotranslationally. Second, DUBs recycle ubiquitin that may have been accidentally trapped by the reaction of small cellular nucleophiles with the thiol ester intermediates involved in the ubiquitination of proteins. Third, DUBs reverse the ubiquitination or ubiquitin-like modification of target proteins. Fourth, DUBs are also responsible for the regeneration of monoubiquitin from unanchored polyubiquitin, i.e., free polyubiquitin that is synthesized de novo by the conjugating machinery or that has been released from target proteins by other DUBs. Finally, the deubiquitinating enzymes UCH-L3 and YUH1 are able to hydrolyse mutant ubiquitin UBB+1 despite of the fact that the glycine at position 76 is mutated.
DUSP domain solution structure of the dusp domain of husp15 Identifiers Symbol DUSP Pfam PF06337 InterPro IPR006615 MEROPS C19 Available protein structures: Pfam structures PDB RCSB PDB; PDBe PDBsum structure summary
All DUBs contain a catalytic domain surrounded by one or more subdomains, some of which contribute to target recognition. The ~120-residue DUSP (domain present in ubiquitin-specific proteases) domain is one of these specific subdomains. Single or tandem DUSP domains are located both N- and C-terminal to the ubiquitin carboxyl-terminal hydrolase catalytic core domain. The DUSP domain displays a tripod-like AB3 fold with a three-helix bundle and a three-stranded anti-parallel beta-sheet resembling the legs and seat of the tripod. Conserved residues are predominantly involved in hydrophobic packing interactions within the three alpha-helices. The most conserved DUSP residues, forming the PGPI motif, are flanked by two long loops that vary both in length and sequence. The PGPI motif packs against the three-helix bundle and is highly ordered. The function of the DUSP domain is unknown but it may play a role in protein/protein interaction or substrate recognition.
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Protein targeting UbiquitinBIRC6 • UFC1 Other see also posttranslational modification disorders
B bsyn: dna (repl, cycl, reco, repr) · tscr (fact, tcrg, nucl, rnat, rept, ptts) · tltn (risu, pttl, nexn) · dnab, rnab/runp · stru (domn, 1°, 2°, 3°, 4°)
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