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Distinct USP25 and USP28 oligomerization states regulate deubiquitinating activity

DOI: 10.1016/j.molcel.2019.02.030 DOI Help

Authors: Malte Gersch (Medical Research Council Laboratory of Molecular Biology; Max-Planck-Institute of Molecular Physiology; Technical University Dortmund) , Jane L. Wagstaff (Medical Research Council Laboratory of Molecular Biology) , Angela V. Toms (FORMA Therapeutics) , Bradford Graves (FORMA Therapeutics) , Stefan M. V. Freund (Medical Research Council Laboratory of Molecular Biology) , David Komander (Medical Research Council Laboratory of Molecular Biology; The Walter and Eliza Hall Institute of Medical Research; The University of Melbourne)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Molecular Cell

State: Published (Approved)
Published: March 2019

Open Access 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 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.

Journal Keywords: ubiquitin; deubiquitylating enzyme; ubiquitin specific proteasec-MYC; TRAF

Subject Areas: Biology and Bio-materials

Instruments: B21-High Throughput SAXS , I02-Macromolecular Crystallography , I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength)

Other Facilities: ESRF