Higher-Order Assembly of BRCC36-KIAA0157 Is Required for DUB Activity and Biological Function.

Molecular Cell
Elton ZeqirajFrank Sicheri

Abstract

BRCC36 is a Zn(2+)-dependent deubiquitinating enzyme (DUB) that hydrolyzes lysine-63-linked ubiquitin chains as part of distinct macromolecular complexes that participate in either interferon signaling or DNA-damage recognition. The MPN(+) domain protein BRCC36 associates with pseudo DUB MPN(-) proteins KIAA0157 or Abraxas, which are essential for BRCC36 enzymatic activity. To understand the basis for BRCC36 regulation, we have solved the structure of an active BRCC36-KIAA0157 heterodimer and an inactive BRCC36 homodimer. Structural and functional characterizations show how BRCC36 is switched to an active conformation by contacts with KIAA0157. Higher-order association of BRCC36 and KIAA0157 into a dimer of heterodimers (super dimers) was required for DUB activity and interaction with targeting proteins SHMT2 and RAP80. These data provide an explanation of how an inactive pseudo DUB allosterically activates a cognate DUB partner and implicates super dimerization as a new regulatory mechanism underlying BRCC36 DUB activity, subcellular localization, and biological function.

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Citations

Jul 5, 2016·Frontiers in Genetics·Shane M Harding, Roger A Greenberg
Nov 12, 2016·BMC Biology·Patrick A Eyers, James M Murphy
Dec 24, 2016·Cell Reports·Otto J P KyrieleisStephen J Smerdon
Mar 1, 2017·Nature Chemical Biology·Jing LiRaymond J Deshaies
May 2, 2017·Nature Chemical Biology·Linda LauingerAxel Diernfellner
May 13, 2017·Annual Review of Biochemistry·Tycho E T Mevissen, David Komander
May 10, 2017·Journal of Cell Science·Pawel Leznicki, Yogesh Kulathu
Feb 24, 2018·Biochemical Society Transactions·Miriam WaldenElton Zeqiraj
Apr 15, 2017·Biochemical Society Transactions·James M MurphyPatrick A Eyers
Jun 12, 2016·The Journal of Biological Chemistry·Hoi-Man NgMichael S Y Huen
Sep 6, 2019·Inflammation Research : Official Journal of the European Histamine Research Society ... [et Al.]·Mohit SinghUmesh C S Yadav
Jul 14, 2018·Nature Communications·Adrian C D FuchsJörg Martin
May 31, 2019·Nature·Miriam WaldenElton Zeqiraj
Jun 30, 2019·Molecular Cell·Julius RablNicolas H Thomä

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Methods Mentioned

BETA
X-ray
light scattering
protein folding
co-immunoprecipitation
co-IP
transfection

Software Mentioned

ProtParam
CRYSOL

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