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

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

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37 Citations (Scopus)
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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.
Original languageEnglish
Article number3814
Pages (from-to)1-13
JournalNature Communications
Issue number1
Early online date23 Aug 2019
Publication statusPublished - 1 Dec 2019


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