Lingaraju Gondichatnahalli, Manjappa, Bunker, Richard, Renatus, Martin, Hassiepen, Ulrich, Thomae, Nicolas, Fischer, Eric, Cavadini, Simone and Hess, Daniel (2014) Crystal structure of the human COP9 signalosome holoenzyme. Nature, 512 (7513). pp. 161-165. ISSN 0028-08361476-4687

Abstract

Ubiquitination is a key cellular signaling event, subject to regulation on multiple levels. Cullin-RING E3 ubiquitin ligases (CRLs) are regulated by the eight-subunit COP9 signalosome (CSN). CSN inactivates CRLs by removing the covalently-attached activator, NEDD8. NEDD8 cleavage by CSN is catalysed by subunit 5 (CSN5), a Zn2+-dependent isopeptidase that is inactive in isolation. It is presently unclear how CSN5 is activated and specificity is conferred for neddylated-CRLs when embedded in its holoenzyme. Here, we present the crystal structure of the entire 350 kDa human CSN holoenzyme at 3.8 Å resolution, providing the detailed molecular architecture of the complex. CSN features two organizational centers; a horseshoe-shaped ring of PCI domains (proteasome-COP9-initiation factor-3), and a large bundle of helices formed by the C-terminal helices of all subunits. CSN5 and its dimerization partner CSN6 are intricately embedded at the core of the bundle and make extensive interactions with all other subunits. In the substrate-free holoenzyme, CSN5 is in an autoinhibited state, which precludes access to the active site. We find that neddylated-CRL binding to CSN is sensed by CSN4, and communicated through CSN6 to CSN5 resulting in activation of the deneddylase.

Item Type:	Article
Keywords:	X-ray structure, protease, Cullin RING ligase, protein complex
Date Deposited:	18 May 2016 23:45
Last Modified:	04 Jul 2016 23:45
URI:	https://oak.novartis.com/id/eprint/20670