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

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

  • Mol Cell. 2015 Sep 17;59(6):970-83. doi: 10.1016/j.molcel.2015.07.028.
Elton Zeqiraj 1,  Lei Tian 2,  Christopher A Piggott 1,  Monica C Pillon 3,  Nicole M Duffy 1,  Derek F Ceccarelli 1,  Alexander F A Keszei 4,  Kristina Lorenzen 1,  Igor Kurinov 5,  Stephen Orlicky 1,  Gerald D Gish 1,  Albert J R Heck 6,  Alba Guarné 3,  Roger A Greenberg 7,  Frank Sicheri 8
Affiliations

Affiliations

  • 1 Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Room 1090, Toronto, ON M5G 1X5, Canada.
  • 2 Departments of Cancer Biology and Pathology, Abramson Family Cancer Research Institute, Basser Research Center for BRCA, Perelman School of Medicine, University of Pennsylvania, 421 Curie Boulevard, Philadelphia, PA 19104-6160, USA.
  • 3 Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4K1, Canada.
  • 4 Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Room 1090, Toronto, ON M5G 1X5, Canada; Departments of Biochemistry and Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
  • 5 Department of Chemistry and Chemical Biology, NE-CAT, Cornell University, Argonne, IL 60439, USA.
  • 6 Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Science, Utrecht University, Padualaan 8, 3584 CH, Utrecht, the Netherlands.
  • 7 Departments of Cancer Biology and Pathology, Abramson Family Cancer Research Institute, Basser Research Center for BRCA, Perelman School of Medicine, University of Pennsylvania, 421 Curie Boulevard, Philadelphia, PA 19104-6160, USA. Electronic address: rogergr@mail.med.upenn.edu.
  • 8 Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Room 1090, Toronto, ON M5G 1X5, Canada; Departments of Biochemistry and Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address: sicheri@lunenfeld.ca.
PMID: 26344097 DOI: 10.1016/j.molcel.2015.07.028
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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