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Cullin-RING ubiquitin E3 ligase regulation by the COP9 signalosome

Cavadini, Simone and Fischer, Eric S. and Bunker, Richard D. and Potenza, Alessandro and Lingaraju, Gondichatnahalli M. and Goldie, Kenneth N. and Mohamed, Weaam I. and Faty, Mahamadou and Petzold, Georg and Beckwith, Rohan E. J. and Tichkule, Ritesh B. and Hassiepen, Ulrich and Abdulrahman, Wassim and Pantelic, Radosav S. and Matsumoto, Syota and Sugasawa, Kaoru and Stahlberg, Henning and Thomä, Nicolas H.. (2016) Cullin-RING ubiquitin E3 ligase regulation by the COP9 signalosome. Nature, 531 (7596). pp. 598-603.

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Official URL: http://edoc.unibas.ch/42182/

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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.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Structural Biology & Biophysics > Structural Biology (Stahlberg)
UniBasel Contributors:Stahlberg, Henning
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Macmillan
ISSN:0028-0836
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:22 Nov 2016 07:02
Deposited On:22 Nov 2016 07:02

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