2y6e
Structure of the D1D2 domain of USP4, the conserved catalytic domain
Structural highlights
FunctionUBP4_HUMAN Hydrolase that deubiquitinates target proteins such as the receptor ADORA2A, PDPK1 and TRIM21. Deubiquitination of ADORA2A increases the amount of functional receptor at the cell surface. Plays a role in the regulation of quality control in the ER.[1] [2] [3] [4] Publication Abstract from PubMedUbiquitin-specific protease USP4 is emerging as an important regulator of cellular pathways, including the TGF-beta response, NF-kappaB signalling and splicing, with possible roles in cancer. Here we show that USP4 has its catalytic triad arranged in a productive conformation. Nevertheless, it requires its N-terminal DUSP-Ubl domain to achieve full catalytic turnover. Pre-steady-state kinetics measurements reveal that USP4 catalytic domain activity is strongly inhibited by slow dissociation of ubiquitin after substrate hydrolysis. The DUSP-Ubl domain is able to enhance ubiquitin dissociation, hence promoting efficient turnover. In a mechanism that requires all USP4 domains, binding of the DUSP-Ubl domain promotes a change of a switching loop near the active site. This 'allosteric regulation of product discharge' provides a novel way of regulating deubiquitinating enzymes that may have relevance for other enzyme classes. The DUSP-Ubl domain of USP4 enhances its catalytic efficiency by promoting ubiquitin exchange.,Clerici M, Luna-Vargas MP, Faesen AC, Sixma TK Nat Commun. 2014 Nov 18;5:5399. doi: 10.1038/ncomms6399. PMID:25404403[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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