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Specificity, plasticity and regulation of cullin-RING ubiquitin E3 ligases by the COP9 signalosome

Cavadini, Simone and Fischer, Eric and Goldie, Kenneth and Bohm, Kerstin and Lingaraju Gondichatnahalli, Manjappa and Jones, Matthew and Bunker, Richard and Faty, Mahamadou and Tichkule, Ritesh and Patelic, Radosav and Mohamed, Weaam and Hassiepen, Ulrich and Beckwith, Rohan and Stahlberg, Henning and Thomae, Nicolas (2014) Specificity, plasticity and regulation of cullin-RING ubiquitin E3 ligases by the COP9 signalosome. Nature.

Abstract

Specificity in the ubiquitin-proteasome system is largely conferred by ubiquitin E3 ligases (E3s). Cullin-RING ligases (CRLs) constitute ~ 1/3 of all E3s in humans and together act on ~20% of the proteins processed by the proteasome1. CRLs are divided into six families based on their cullin constituent (either CUL1, CUL2, CUL3, CUL4A/B or CUL5). Each cullin binds a RING-domain containing protein (RBX1 or RBX2) and a vast repertoire of adaptor/substrate receptor modules, collectively creating ~240 distinct CRLs2. All CRLs are regulated by the COP9 signalosome (CSN), an eight-protein isopeptidase (CSN1-8) that removes the covalently attached activator, NEDD8, from the cullin3-5. Independent of NEDD8 cleavage, CSN forms protective complexes with CRLs that prevent autoubiquitination6,7, limiting their turnover8. Here, we present single-particle electron microscopy (EM) structures for CSN in complex with representatives of the CRL4 family and a dimeric CRL3, demonstrating how CSN binds and regulates structurally diverse CRLs. Despite striking differences among CRLs, CSN engages the cullin C-terminal domain (CULCTD) in a conserved manner. The interactions between CSN and the variety of CRL adaptor/substrate receptor modules, however, differ. CSN inactives CRLs by shielding them from ubiquitin-conjugating enzymes (E2s). When in complex with CSN, the conformation of the cullin assembly adjusts to space the substrate receptors uniformly ~15-20 Å from CSN, leaving the CRL substrate binding site accessible. We show that the size of the bound CRL substrate, not its identity triggers CSN release, freeing the CRL from CSN inhibition. This mechanism protects CRLs from autoubiquitination in the absence of substrate, and releases CSN inhibition once the ligase encounters a substrate.

Item Type: Article
Keywords: Please note that during review this manuscript was divided into two and published as two papers: Nature 2016, 531, 598 & Nature 2014, 512, 49.
Date Deposited: 28 Apr 2016 23:45
Last Modified: 28 Apr 2016 23:45
URI: https://oak.novartis.com/id/eprint/22217

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