| Primary Identifier | IPR019400 | Type | Family |
| Short Name | Peptidase_C65_otubain |
| description | This family comprises highly specific ubiquitin isopeptidases (otubains) that remove 'Lys-48'-linked, but not 'Lys-63'-linked, polyubiquitin chains from substrate proteins, regulating protein turnover by preventing degradation [, ]. Family members cannot cleave di-ubiquitin directly and can also remove NEDD8 from NEDD8 conjugates, albeit with lower efficiency than ubiquitin [, ]. The catalytic OTU (ovarian tumour) domain contains a cysteine protease triad and is accompanied by a nuclear localisation signal, a ubiquitin-interaction motif (UIM)-like motif (phi-xx-A-xxxs-xx-Ac, where phi is an aromatic residue, x is any residue and Ac is an acidic residue), a ubiquitin-associated (UBA)-like domain and an LxxLL motif [].Beyond its catalytic activity, the best-characterised member, OTUB1, also acts non-catalytically: it binds and inhibits the E2 enzyme UBE2N/UBC13, blocking RNF168-mediated spreading of 'Lys-63'-linked histone H2A/H2AX ubiquitination at DNA damage sites [, ], and regulates mTORC1/mTORC2 signalling by controlling ubiquitination of RPTOR and DEPTOR [, ]. It further regulates T-cell anergy through isoform-specific interaction with the E3 ligase RNF128/GRAIL []and deubiquitinates substrates such as estrogen receptor alpha []. OTU domain activity is allosterically enhanced by binding of free ubiquitin [, ]. |
