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The molecular basis of cullin substrate recognition by the COP9 signalosome (CSN)

Applicant Thomä Nicolas
Number 144020
Funding scheme Project funding (Div. I-III)
Research institution Friedrich Miescher Institute for Biomedical Research
Institution of higher education Institute Friedrich Miescher - FMI
Main discipline Biochemistry
Start/End 01.10.2012 - 30.09.2015
Approved amount 445'000.00
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All Disciplines (4)

Discipline
Biochemistry
Cellular Biology, Cytology
Biophysics
Molecular Biology

Keywords (7)

Cullin; CSN; Structural biology; DNA repair; E3 Ubiquitin ligases; Ubiquitination; COP9 signalosome

Lay Summary (English)

Lead
Lay summary
The ubiquitin transferase system represents the major system for targeted protein degradation in the cell. The cullin-RING type E3 ligases (CRL) account for about 30% of these ligases. Regulation of the CRL system is via attachment of a small ubiquitin-like modifier (NEDD8). De-neddylation is carried out by the COP9 signalosome (CSN). We propose to study the structure and function of CSN through a combination of structural techniques, cell biology and biochemistry. The focus will be on understanding the role of individual subunits in the assembly, activity and regulation of this macromolecular complex.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Crystal structure of the human COP9 signalosome
Lingaraju Gondichatnahalli M., Lingaraju Gondichatnahalli M., Bunker Richard D., Bunker Richard D., Cavadini Simone, Cavadini Simone, Hess Daniel, Hassiepen Ulrich, Renatus Martin, Fischer Eric S., Fischer Eric S., Thomä Nicolas H., Thomä Nicolas H. (2014), Crystal structure of the human COP9 signalosome, in Nature, 512(7513), 161-165.

Abstract

We aim to focus on the molecular mechanism of COP9 signalosome function, examining ways by which it regulates cullin type E3 ubiquitin ligases. The COP9 signalosome (CSN) is composed of 8-subunits, and has structural resemblance to eIF3 and the 26S proteasome lid. CSN functions as an isopeptidase through its CSN5 subunit, with which it removes the ubiquitin-like NEDD8 modifier from the cullin arm. NEDD8 is considered an activator; its removal renders the ligase complex inactive. The signalosome serves as master repressor of cullin type E3 ligases (incl. CUL1, CUL2, CUL3, CUL4, CUL5 and CUL7 families). We will pursue a structural approach examining how the signalosome serves to regulate and inhibit different, structurally diverse, families of cullin ligases.
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