6HEM

Structure of the C-terminal domain of USP25 (748-1048)

Summary for 6HEM

• Entry DOI: 10.2210/pdb6hem/pdb
• Descriptor: Ubiquitin carboxyl-terminal hydrolase 25, GLYCEROL, SODIUM ION, ... (4 entities in total)
• Functional Keywords: ubiquitin, usp, ubiquitin-specific protease, dub, deubiquitinase, protease, isopeptidase, usp25, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 36124.14

Authors

Gersch, M.,Komander, D. (deposition date: 2018-08-20, release date: 2019-03-27, Last modification date: 2024-05-15)

Primary citation

Gersch, M.,Wagstaff, J.L.,Toms, A.V.,Graves, B.,Freund, S.M.V.,Komander, D.
Distinct USP25 and USP28 Oligomerization States Regulate Deubiquitinating Activity.
Mol.Cell, 74:436-, 2019

PubMed 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 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.

PubMed: 30926242
DOI: 10.1016/j.molcel.2019.02.030

Experimental method

X-RAY DIFFRACTION (1.72 Å)