Abstract
SummaryBRCC36 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. 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 the first 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.
Highlights
Ubiquitin-mediated signal transduction depends on a balance between tightly regulated ubiquitin ligase and deubiquitinating enzyme (DUB) activities (Komander and Rape, 2012; Komander et al, 2009)
The MPN+ domain protein BRCC36 associates with pseudo DUB MPN– proteins KIAA0157 or Abraxas, which are essential for BRCC36 enzymatic activity
Higher-order association of BRCC36 and KIAA0157 into a dimer of heterodimers 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
Summary
Ubiquitin-mediated signal transduction depends on a balance between tightly regulated ubiquitin ligase and deubiquitinating enzyme (DUB) activities (Komander and Rape, 2012; Komander et al, 2009). The Abraxas complex (ARISC) functions in DNA repair and breast cancer suppression, while the BRCC36 isopeptidase complex (BRISC) promotes interferon-dependent responses by deubiquitinating and stabilizing the type I interferon receptor, IFNAR1 Both BRCC36 complexes demonstrate tightly regulated DUB activity involving protein-protein interactions with their pseudo DUB subunits and with targeting proteins SHMT2 or RAP80. The latter two target the complexes to K63-Ub chains that are synthesized locally in response to cytokine receptor activation for BRISC or DNA double-strand breaks (DSBs) for ARISC (Kim et al, 2007; Sobhian et al, 2007; Wang et al, 2007; Zheng et al, 2013)
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