Structural and kinetic analysis of the COP9-Signalosome activation and the cullin-RING ubiquitin ligase deneddylation cycle

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2016
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Mosadeghi, Ruzbeh
Reichermeier, Kurt M.
Winkler, Martin
Schreiber, Anne
Reitsma, Justin M.
Zhang, Yaru
Peter, Matthias
Deshaies, Raymond J.
Enchev, Radoslav I.
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The COP9-Signalosome (CSN) regulates cullin-RING ubiquitin ligase (CRL) activity and assembly by cleaving Nedd8 from cullins. Free CSN is autoinhibited, and it remains unclear how it becomes activated. We combine structural and kinetic analyses to identify mechanisms that contribute to CSN activation and Nedd8 deconjugation. Both CSN and neddylated substrate undergo large conformational changes upon binding, with important roles played by the N-terminal domains of Csn2 and Csn4 and the RING domain of Rbx1 in enabling formation of a high affinity, fully active complex. The RING domain is crucial for deneddylation, and works in part through conformational changes involving insert-2 of Csn6. Nedd8 deconjugation and re-engagement of the active site zinc by the autoinhibitory Csn5 glutamate-104 diminish affinity for Cul1/Rbx1 by ~100-fold, resulting in its rapid ejection from the active site. Together, these mechanisms enable a dynamic deneddylation-disassembly cycle that promotes rapid remodeling of the cellular CRL network.

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ISO 690MOSADEGHI, Ruzbeh, Kurt M. REICHERMEIER, Martin WINKLER, Anne SCHREIBER, Justin M. REITSMA, Yaru ZHANG, Florian STENGEL, Matthias PETER, Raymond J. DESHAIES, Radoslav I. ENCHEV, 2016. Structural and kinetic analysis of the COP9-Signalosome activation and the cullin-RING ubiquitin ligase deneddylation cycle. In: eLife. 2016, 5, e12102. eISSN 2050-084X. Available under: doi: 10.7554/eLife.12102
BibTex
@article{Mosadeghi2016Struc-35495,
  year={2016},
  doi={10.7554/eLife.12102},
  title={Structural and kinetic analysis of the COP9-Signalosome activation and the cullin-RING ubiquitin ligase deneddylation cycle},
  volume={5},
  journal={eLife},
  author={Mosadeghi, Ruzbeh and Reichermeier, Kurt M. and Winkler, Martin and Schreiber, Anne and Reitsma, Justin M. and Zhang, Yaru and Stengel, Florian and Peter, Matthias and Deshaies, Raymond J. and Enchev, Radoslav I.},
  note={Article Number: e12102}
}
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