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

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Zeqiraj E, Tian L, Piggott CA, Pillon MC, Duffy NM, Ceccarelli DF, Keszei AF, Lorenzen K, Kurinov I, Orlicky S, Gish GD, Heck AJ, Guarne A, Greenberg RA, Sicheri F

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. Epub 2015 Sep 3.

PubMed ID

26344097 [ View in PubMed

]

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.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Zinc	Lys-63-specific deubiquitinase BRCC36	Protein	Humans	Unknown	Not Available	Details
Zinc acetate	Lys-63-specific deubiquitinase BRCC36	Protein	Humans	Unknown	Not Available	Details
Zinc chloride	Lys-63-specific deubiquitinase BRCC36	Protein	Humans	Unknown	Cofactor	Details
Zinc sulfate, unspecified form	Lys-63-specific deubiquitinase BRCC36	Protein	Humans	Unknown	Cofactor	Details

Polypeptides

Name	UniProt ID
Lys-63-specific deubiquitinase BRCC36	P46736	Details