Cullin–RING ubiquitin E3 ligase regulation by the COP9 signalosome

Simone Cavadini, Eric S. Fischer, Richard D. Bunker, Alessandro Potenza, Gondichatnahalli M. Lingaraju, Kenneth N. Goldie, Weaam I. Mohamed, Mahamadou Faty, Georg Petzold, Rohan E. J. Beckwith, Ritesh B. Tichkule, Ulrich Hassiepen, Wassim Abdulrahman, Radosav S. Pantelic, Syota Matsumoto, Kaoru Sugasawa, Henning Stahlberg and Nicolas H. Thomä ()
Additional contact information
Simone Cavadini: Friedrich Miescher Institute for Biomedical Research
Eric S. Fischer: Friedrich Miescher Institute for Biomedical Research
Richard D. Bunker: Friedrich Miescher Institute for Biomedical Research
Alessandro Potenza: Friedrich Miescher Institute for Biomedical Research
Gondichatnahalli M. Lingaraju: Friedrich Miescher Institute for Biomedical Research
Kenneth N. Goldie: Center for Cellular Imaging and NanoAnalytics, Biozentrum, University of Basel
Weaam I. Mohamed: Friedrich Miescher Institute for Biomedical Research
Mahamadou Faty: Friedrich Miescher Institute for Biomedical Research
Georg Petzold: Friedrich Miescher Institute for Biomedical Research
Rohan E. J. Beckwith: Novartis Institutes for Biomedical Research
Ritesh B. Tichkule: Novartis Institutes for Biomedical Research
Ulrich Hassiepen: Novartis Pharma AG, Institutes for Biomedical Research, Novartis Campus
Wassim Abdulrahman: Friedrich Miescher Institute for Biomedical Research
Radosav S. Pantelic: Center for Cellular Imaging and NanoAnalytics, Biozentrum, University of Basel
Syota Matsumoto: Biosignal Research Center, Organization of Advanced Science and Technology, Kobe University
Kaoru Sugasawa: Biosignal Research Center, Organization of Advanced Science and Technology, Kobe University
Henning Stahlberg: Center for Cellular Imaging and NanoAnalytics, Biozentrum, University of Basel
Nicolas H. Thomä: Friedrich Miescher Institute for Biomedical Research

Nature, 2016, vol. 531, issue 7596, 598-603

Abstract: Abstract 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 (CRL4ADDB2) monitors the genome for ultraviolet-light-induced DNA damage. CRL4ADBB2 is inactive in the absence of damaged DNA and requires CSN to regulate the repair process. The structural basis of CSN binding to CRL4ADDB2 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.

Date: 2016
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DOI: 10.1038/nature17416

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