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Title: Higher-order assembly of BRCC36–KIAA0157 is required for DUB activity and biological function

BRCC36 is a Zn2+-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. Here, 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. Lastly, 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.
Authors:
 [1] ;  [2] ;  [1] ;  [3] ;  [1] ;  [1] ;  [4] ;  [1] ;  [5] ;  [1] ;  [1] ;  [6] ;  [3] ;  [2] ;  [4]
  1. Mount Sinai Hospital, Toronto, ON (Canada). Lunenfeld-Tanenbaum Research Inst.
  2. Univ. of Pennsylvania, Philadelphia, PA (United States). Perelman School of Medicine, Basser Research Center for BRCA, Abramson Family Cancer Research Inst., Dept. of Cancer Biology and Pathology
  3. McMaster Univ., Hamilton, ON (Canada). Dept. of Biochemistry and Biomedical Sciences
  4. Mount Sinai Hospital, Toronto, ON (Canada). Lunenfeld-Tanenbaum Research Inst.; Univ. of Toronto, ON (Canada). Dept. of Biochemistry and Molecular Genetics
  5. Cornell Univ., Argonne, IL (United States). Dept. of Chemistry and Chemical Biology
  6. Univ. of Utrecht (Netherlands). Bijvoet Center for Biomolecular Research and Utrecht Inst. for Pharmaceutical Science
Publication Date:
OSTI Identifier:
1250984
Grant/Contract Number:
AC02-06CH11357; S10 RR029205; CA138835; CA17494; GM101149; P41 GM103403; MOP-126129; MOP-57795
Type:
Published Article
Journal Name:
Molecular Cell
Additional Journal Information:
Journal Volume: 59; Journal Issue: 6; Journal ID: ISSN 1097-2765
Publisher:
Elsevier - Cell Press
Research Org:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org:
USDOE Office of Science (SC); National Institutes of Health (NIH); Canadian Institutes of Health; Abramson Family Cancer Research Institute; Basser Research Center
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES