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

Journal Article · Tue Sep 01 00:00:00 EDT 2015 · Molecular Cell

DOI:https://doi.org/10.1016/j.molcel.2015.07.028· OSTI ID:1250984

Zeqiraj, Elton; Tian, Lei; Piggott, Christopher A.; Pillon, Monica C.; Duffy, Nicole M.; Ceccarelli, Derek F.; Keszei, Alexander F. A.; Lorenzen, Kristina; Kurinov, Igor; Orlicky, Stephen; Gish, Gerald D.; Heck, Albert J. R.; Guarné, Alba; Greenberg, Roger A.; Sicheri, Frank

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.

• Research Organization: Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
• Sponsoring Organization: USDOE Office of Science (SC); National Institutes of Health (NIH); Canadian Institutes of Health; Abramson Family Cancer Research Institute; Basser Research Center
• Grant/Contract Number: AC02-06CH11357; S10 RR029205; CA138835; CA17494; GM101149; P41 GM103403; MOP-126129; MOP-57795
• OSTI ID: 1250984
• Alternate ID(s): OSTI ID: 1222836
• Journal Information: Molecular Cell, Journal Name: Molecular Cell Vol. 59 Journal Issue: 6; ISSN 1097-2765
• Publisher: Elsevier
• Country of Publication: United States
• Language: English

Related Subjects

59 BASIC BIOLOGICAL SCIENCES