Journal article
Distinct USP25 and USP28 Oligomerization States Regulate Deubiquitinating Activity
M Gersch, JL Wagstaff, AV Toms, B Graves, SMV Freund, D Komander
Molecular Cell | CELL PRESS | Published : 2019
Open access
Abstract
The 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 oli..
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Awarded by Lister Institute of Preventive Medicine
Funding Acknowledgements
We thank beamline scientists at Diamond Light Source (DLS) for support at beamlines I02, I03, I04-1, and B21 and at the European Synchrotron Radiation Facility (ESRF) for support at beamlines ID29 and ID30B. Access to DLS was supported in part by the EU FP7 infrastructure grant BIOSTRUCT-X (contract no. 283570). We are grateful to Farid El Oualid (UbiQ) and Paul Geurink and Huib Ovaa (LUMC) for reagents; to Sylvie Urbe and Michael Clague (Liverpool) for discussions and reagents; to Robert Rambo and Nathan Cowieson (DLS) for support during SAXS data collections; to Ingo Greger (MRC LMB) and Janet Deane (CIMR) for access to F-SEC and SEC-MALS chromatography systems; to Andrew Leslie and Alexey Murzin (MRC LMB) for discussions; to members of the Komander lab, in particular Jonathan Pruneda, Paul Elliott, and Rune Busk Damgaard; to the DUB Alliance; and to MRC LMB for reagents, discussions, and advice. This work was supported by the Medical Research Council (U105192732), the European Research Council (724804), and the Lister Institute for Preventive Medicine. M.G. was supported through a College Post-Doctoral Associateship by Jesus College, Cambridge.