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

• DOI: 10.1016/j.molcel.2015.07.028
• Publication Date: 2015-09-04T00:12:04Z
• Authors: Elton Zeqiraj; Lei Tian; Christopher A. Pi...; Monica C. Pillon; Nicole M. Duffy; Derek F. Ceccarelli; Alexander F.A. Ke...; Kristina Lorenzen; Igor Kurinov; Stephen Orlicky; Gerald D. Gish; Albert J.R. Heck; Alba Guarné; Roger A. Greenberg; Frank Sicheri
• Keywords: Deubiquitinating enzyme

BRCC36 is a Zn2+-dependent deubiquitinating enzyme (DUB) that hydrolyzes lysine-63-linked ubiquitin chains as part of distinct macromolecular complexes participate in either interferon signaling or DNA-damage recognition. The MPN+ domain protein associates with pseudo DUB MPN– proteins KIAA0157 Abraxas, which are essential for enzymatic activity. To understand the basis regulation, we have solved structure an active BRCC36-KIAA0157 heterodimer and inactive homodimer. Structural functional characterizations show how switched to conformation by contacts KIAA0157. Higher-order association into dimer heterodimers (super dimers) was required activity interaction targeting SHMT2 RAP80. These data provide explanation allosterically activates cognate partner implicates super dimerization new regulatory mechanism underlying activity, subcellular localization, biological function.