6R7H

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

Summary for 6R7H

• Entry DOI: 10.2210/pdb6r7h/pdb
• EMDB information: 4741
• Descriptor: COP9 signalosome complex subunit 1, COP9 signalosome complex subunit 7b, COP9 signalosome complex subunit 8, ... (12 entities in total)
• Functional Keywords: cullin-ring e3 ligases (crls) cop9 signalosome (csn) deneddylation, ligase
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 12
• Total formula weight: 414385.98

Authors

Faull, S.V.,Lau, A.M.C.,Beuron, F.,Cronin, N.B.,Morris, E.P.,Politis, A. (deposition date: 2019-03-28, release date: 2019-08-28, Last modification date: 2024-05-22)

Primary citation

Faull, S.V.,Lau, A.M.C.,Martens, C.,Ahdash, Z.,Hansen, K.,Yebenes, H.,Schmidt, C.,Beuron, F.,Cronin, N.B.,Morris, E.P.,Politis, A.
Structural basis of Cullin 2 RING E3 ligase regulation by the COP9 signalosome.
Nat Commun, 10:3814-3814, 2019

PubMed 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.

PubMed: 31444342
DOI: 10.1038/s41467-019-11772-y

Experimental method

ELECTRON MICROSCOPY (8.8 Å)