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

Ruzbeh Mosadeghi, Kurt M. Reichermeier, Martin Winkler, Anne Schreiber, Justin M. Reitsma, Yaru Zhang, Florian Stengel, Junyue Cao, Minsoo Kim, Michael J. Sweredoski, Sonja Hess, Alexander Leitner, Ruedi Aebersold, Matthias Peter, Raymond J. Deshaies, Radoslav I. Enchev
doi: https://doi.org/10.1101/046367
Ruzbeh Mosadeghi
1Keck School of Medicine of the University of Southern California/California Institute of Technology Combined MD/PhD Program
2Division of Biology and Biological Engineering, California Institute of Technology, Pasadena CA, USA, 911250
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Kurt M. Reichermeier
2Division of Biology and Biological Engineering, California Institute of Technology, Pasadena CA, USA, 911250
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Martin Winkler
3Department of Biology, Institute of Biochemistry, Swiss Federal Institute of Technology, Otto-Stern Weg 3, 8093 Zürich, Switzerland
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Anne Schreiber
3Department of Biology, Institute of Biochemistry, Swiss Federal Institute of Technology, Otto-Stern Weg 3, 8093 Zürich, Switzerland
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Justin M. Reitsma
2Division of Biology and Biological Engineering, California Institute of Technology, Pasadena CA, USA, 911250
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Yaru Zhang
2Division of Biology and Biological Engineering, California Institute of Technology, Pasadena CA, USA, 911250
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Florian Stengel
4Department of Biology, Institute of Molecular Systems Biology, Swiss Federal Institute of Technology, HPT E 78, August-Piccard-Hof 1, 8093 Zürich, Switzerland
8Current Address - Department of Biology, University of Konstanz, 78457 Konstanz, Germany
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Junyue Cao
2Division of Biology and Biological Engineering, California Institute of Technology, Pasadena CA, USA, 911250
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Minsoo Kim
2Division of Biology and Biological Engineering, California Institute of Technology, Pasadena CA, USA, 911250
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Michael J. Sweredoski
5Proteome Exploration Lab, Beckman Institute, California Institute of Technology, Pasadena CA, USA, 91125
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Sonja Hess
5Proteome Exploration Lab, Beckman Institute, California Institute of Technology, Pasadena CA, USA, 91125
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Alexander Leitner
4Department of Biology, Institute of Molecular Systems Biology, Swiss Federal Institute of Technology, HPT E 78, August-Piccard-Hof 1, 8093 Zürich, Switzerland
8Current Address - Department of Biology, University of Konstanz, 78457 Konstanz, Germany
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Ruedi Aebersold
4Department of Biology, Institute of Molecular Systems Biology, Swiss Federal Institute of Technology, HPT E 78, August-Piccard-Hof 1, 8093 Zürich, Switzerland
6Faculty of Science, University of Zurich, Zurich, Switzerland
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Matthias Peter
3Department of Biology, Institute of Biochemistry, Swiss Federal Institute of Technology, Otto-Stern Weg 3, 8093 Zürich, Switzerland
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Raymond J. Deshaies
2Division of Biology and Biological Engineering, California Institute of Technology, Pasadena CA, USA, 911250
7Howard Hughes Medical Institute
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Radoslav I. Enchev
3Department of Biology, Institute of Biochemistry, Swiss Federal Institute of Technology, Otto-Stern Weg 3, 8093 Zürich, Switzerland
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Abstract

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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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted March 30, 2016.
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Structural and kinetic analysis of the COP9-Signalosome activation and the cullin-RING ubiquitin ligase deneddylation cycle
Ruzbeh Mosadeghi, Kurt M. Reichermeier, Martin Winkler, Anne Schreiber, Justin M. Reitsma, Yaru Zhang, Florian Stengel, Junyue Cao, Minsoo Kim, Michael J. Sweredoski, Sonja Hess, Alexander Leitner, Ruedi Aebersold, Matthias Peter, Raymond J. Deshaies, Radoslav I. Enchev
bioRxiv 046367; doi: https://doi.org/10.1101/046367
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Structural and kinetic analysis of the COP9-Signalosome activation and the cullin-RING ubiquitin ligase deneddylation cycle
Ruzbeh Mosadeghi, Kurt M. Reichermeier, Martin Winkler, Anne Schreiber, Justin M. Reitsma, Yaru Zhang, Florian Stengel, Junyue Cao, Minsoo Kim, Michael J. Sweredoski, Sonja Hess, Alexander Leitner, Ruedi Aebersold, Matthias Peter, Raymond J. Deshaies, Radoslav I. Enchev
bioRxiv 046367; doi: https://doi.org/10.1101/046367

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