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Cullin–RING ubiquitin E3 ligase regulation by the COP9 signalosome
Open accessAbstract
The cullin-RING ubiquitin E3 ligase (CRL) family comprises over 200 members in humans. The COP9 signalosome complex (CSN) regulates CRLs by removing their ubiquitin-like activator NEDD8. The CUL4A-RBX1-DDB1-DDB2 complex (CRL4A(DDB2)) monitors the genome for ultraviolet-light-induced DNA damage. CRL4A(DBB2) is inactive in the absence of damaged DNA and requires CSN to regulate the repair process. The structural basis of CSN binding to CRL4A(DDB2) and the principles of CSN activation are poorly understood. Here we present cryo-electron microscopy structures for CSN in complex with neddylated CRL4A ligases to 6.4 Å resolution. The CSN conformers defined by cryo-electron microscopy and a novel apo-CSN crystal structure indicate an induced-fit mechanism that drives CSN activation by neddylated CRLs. We find that CSN and a substrate cannot bind simultaneously to CRL4A, favouring a deneddylated, inactive state for substrate-free CRL4 complexes. These architectural and regulatory principles appear conserved across CRL families, allowing global regulation by CSN.
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“it seems likely that the conformational dynamics of unneddylated CRLs (Extended Data Figure 2) would enable transitioning between the different conformations coordinating cycles of neddylation/deneddylation with CAND1-driven substrate-receptor exchange39,46–49.”
From NEDD8 nucleates a multivalent cullin–RING–UBE2D ubiquitin ligation assembly (2020) · cites this paper as [48]
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MethodSelf-citation
Metadata
- Authors
- Cavadini, S., Fischer, E. S., Bunker, R. D., Potenza, A., Lingaraju, G. M., Goldie, K. N., Mohamed, W. I., Faty, M., Petzold, G., Beckwith, R. E. J., Tichkule, R. B., Hassiepen, U., Abdulrahman, W., Pantelic, R. S., Matsumoto, S., Sugasawa, K., Stahlberg, H., & Thomä, N. H.
- Affiliations
- University of Basel (CH)
- Harvard University (US)
- Novartis (Switzerland) (CH)
- Biosignal Research Center, Kobe University (JP)
- Corresponding author
- Thomä, Nicolas H.
- ORCID
- Venue
- Nature
- Published
- 2016-03-30
- Volume
- 531
- Issue
- 7596
- Pages
- 598-603
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2327577222
- Cited by
- 213
- References
- 49
- Citations by year
- 2026: 15 · 2025: 14 · 2024: 16 · 2023: 18 · 2022: 13 · 2021: 25 · 2020: 45 · 2019: 23 · 2018: 14 · 2017: 21 · 2016: 8
- FWCI
- 11.43
- Type
- journal article
- Language
- en
- Open access
- green
- infoscience.epfl.ch
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DORA PSI (Paul Scherrer Institute) (submittedVersion)
- edoc (University of Basel) (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
- Zenodo (CERN European Organization for Nuclear Research) (submittedVersion, other-oa)
- Funders
- Japan Society for the Promotion of Science
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Enzyme Structure and Function
- Keywords
- COP9 signalosome, NEDD8, induced fit, UV-induced DNA damage, DNA repair, protein degradation, substrate binding
- MeSH terms
- COP9 Signalosome Complex, Allosteric Regulation, Apoproteins, Binding Sites, Carrier Proteins, DNA Damage, DNA-Binding Proteins, Humans, Kinetics, Models, Molecular, Peptide Hydrolases, Protein Binding, Ubiquitins, Crystallography, X-Ray, Cryoelectron Microscopy, Cullin Proteins, Multiprotein Complexes, Ubiquitination, Biocatalysis
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