6hel | pdb_00006hel
Structure of human USP25
Structural highlights
Function[UBP25_HUMAN] Deubiquitinating enzyme that hydrolyzes ubiquitin moieties conjugated to substrates and thus, functions to process newly synthesized Ubiquitin, to recycle ubiquitin molecules or to edit polyubiquitin chains and prevents proteasomal degradation of substrates. Hydrolyzes both 'Lys-48'- and 'Lys-63'-linked tetraubiquitin chains. The muscle-specific isoform (USP25m) may have a role in the regulation of muscular differentiation and function. Publication Abstract from PubMedThe evolutionarily related deubiquitinating enzymes (DUBs) USP25 and USP28 comprise an identical overall domain architecture but are functionally non-redundant: USP28 stabilizes c-MYC and other nuclear proteins, and USP25 regulates inflammatory TRAF signaling. We here compare molecular features of USP25 and USP28. Active enzymes form distinctively shaped dimers, with a dimerizing insertion spatially separating independently active catalytic domains. In USP25, but not USP28, two dimers can form an autoinhibited tetramer, where a USP25-specific, conserved insertion sequence blocks ubiquitin binding. In full-length enzymes, a C-terminal domain with a previously unknown fold has no impact on oligomerization, but N-terminal regions affect the dimer-tetramer equilibrium in vitro. We confirm oligomeric states of USP25 and USP28 in cells and show that modulating oligomerization affects substrate stabilization in accordance with in vitro activity data. Our work highlights how regions outside of the catalytic domain enable a conceptually intriguing interplay of DUB oligomerization and activity. Distinct USP25 and USP28 Oligomerization States Regulate Deubiquitinating Activity.,Gersch M, Wagstaff JL, Toms AV, Graves B, Freund SMV, Komander D Mol Cell. 2019 Mar 21. pii: S1097-2765(19)30141-8. doi:, 10.1016/j.molcel.2019.02.030. PMID:30926242[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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