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-Structure paper
タイトル | Structural basis of Cullin 2 RING E3 ligase regulation by the COP9 signalosome. |
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ジャーナル・号・ページ | Nat Commun, Vol. 10, Issue 1, Page 3814, Year 2019 |
掲載日 | 2019年8月23日 |
著者 | Sarah V Faull / Andy M C Lau / Chloe Martens / Zainab Ahdash / Kjetil Hansen / Hugo Yebenes / Carla Schmidt / Fabienne Beuron / Nora B Cronin / Edward P Morris / Argyris Politis / |
PubMed 要旨 | 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. ...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. |
リンク | Nat Commun / PubMed:31444342 / PubMed Central |
手法 | EM (単粒子) |
解像度 | 5.9 - 8.8 Å |
構造データ | EMDB-4736, PDB-6r6h: EMDB-4739, PDB-6r7f: EMDB-4741, PDB-6r7h: |
化合物 | ChemComp-ZN: ChemComp-HOH: |
由来 |
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キーワード | LIGASE / Cullin-Ring E3 Ligase COP9 Signalosome Neddylation / Cullin-Ring E3 Ligases (CRLs) COP9 signalosome (CSN) deneddylation / Cullin-Ring E3 Ligases (CRLs) COP9 signalosome (CSN) deneddylation VHL tumour suppressor substrate receptor |