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Structural basis of Cullin 2 RING E3 ligase regulation by the COP9 signalosome

Research output: Contribution to journalArticle

Sarah V Faull, Andy Lau, Chloe Paule Vinciane Julienne Martens, Zainab Mohamed Ahdash, Kjetil Hansen, Hugo Yebenes, Carla Schmidt, Fabienne Beuron, Nora Cronin, Edward P. Morris, Anargyros Politis

Original languageEnglish
Article number3814
Pages (from-to)1-13
JournalNature Communications
Volume10
Issue number1
Early online date23 Aug 2019
DOIs
Accepted/In press2 Aug 2019
E-pub ahead of print23 Aug 2019
Published1 Dec 2019

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Abstract

Cullin-Ring E3 Ligases (CRLs) regulate a multitude of cellular pathways through specific substrate receptors. The COP9 signalosome (CSN) deactivates CRLs by removing NEDD8 from activated Cullins. Here we present structures of the neddylated and deneddylated CSN- CRL2 complexes by combining single-particle cryo-electron microscopy (cryo-EM) with chemical cross-linking mass spectrometry (XL-MS). These structures suggest a conserved mechanism of CSN activation, consisting of conformational clamping of the CRL2 substrate by CSN2/CSN4, release of the catalytic CSN5/CSN6 heterodimer and finally activation of the CSN5 deneddylation machinery. Using hydrogen-deuterium exchange (HDX)-MS we show that CRL2 activates CSN5/CSN6 in a neddylation-independent manner. The presence of NEDD8 is required to activate the CSN5 active site. Overall, by synergising cryo-EM with MS, we identify sensory regions of the CSN that mediate its stepwise activation and provide a framework for understanding the regulatory mechanism of other Cullin family members.

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