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CsnCRL SIGNED

The molecular basis of CULLIN E3 ligase regulation by the COP9 signalosome

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EC-Contrib. €

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 CsnCRL project word cloud

Explore the words cloud of the CsnCRL project. It provides you a very rough idea of what is the project "CsnCRL" about.

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Project "CsnCRL" data sheet

The following table provides information about the project.

Coordinator
FRIEDRICH MIESCHER INSTITUTE FOR BIOMEDICAL RESEARCH FONDATION 

Organization address
address: MAULBEERSTRASSE 66
city: BASEL
postcode: 4058
website: www.fmi.ch

contact info
title: n.a.
name: n.a.
surname: n.a.
function: n.a.
email: n.a.
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fax: n.a.

 Coordinator Country Switzerland [CH]
 Total cost 2˙200˙677 €
 EC max contribution 2˙200˙677 € (100%)
 Programme 1. H2020-EU.1.1. (EXCELLENT SCIENCE - European Research Council (ERC))
 Code Call ERC-2014-ADG
 Funding Scheme ERC-ADG
 Starting year 2016
 Duration (year-month-day) from 2016-01-01   to  2020-12-31

 Partnership

Take a look of project's partnership.

# participants  country  role  EC contrib. [€] 
1    FRIEDRICH MIESCHER INSTITUTE FOR BIOMEDICAL RESEARCH FONDATION CH (BASEL) coordinator 2˙200˙677.00

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 Project objective

Specificity in the ubiquitin-proteasome system is largely conferred by ubiquitin E3 ligases (E3s). Cullin-RING ligases (CRLs), constituting ~30% of all E3s in humans, mediate the ubiquitination of ~20% of the proteins degraded by the proteasome. CRLs are divided into seven families based on their cullin constituent. Each cullin binds a RING domain protein, and a vast repertoire of adaptor/substrate receptor modules, collectively creating more than 200 distinct CRLs. All CRLs are regulated by the COP9 signalosome (CSN), an eight-protein isopeptidase that removes the covalently attached activator, NEDD8, from the cullin. Independent of NEDD8 cleavage, CSN forms protective complexes with CRLs, which prevents destructive auto-ubiquitination.

The integrity of the CSN-CRL system is crucially important for the normal cell physiology. Based on our previous work on CRL structures (Fischer, et al., Nature 2014; Fischer, et al., Cell 2011) and that of isolated CSN (Lingaraju et al., Nature 2014), We now intend to provide the underlying molecular mechanism of CRL regulation by CSN. Structural insights at atomic resolution, combined with in vitro and in vivo functional studies are designed to reveal (i) how the signalosome deneddylates and maintains the bound ligases in an inactive state, (ii) how the multiple CSN subunits bind to structurally diverse CRLs, and (iii) how CSN is itself subject to regulation by post-translational modifications or additional further factors.

The ERC funding would allow my lab to pursue an ambitious interdisciplinary approach combining X-ray crystallography, cryo-electron microscopy, biochemistry and cell biology. This is expected to provide a unique molecular understanding of CSN action. Beyond ubiquitination, insight into this >13- subunit CSN-CRL assembly will allow examining general principles of multi-subunit complex action and reveal how the numerous, often essential, subunits contribute to complex function.

 Publications

year authors and title journal last update
List of publications.
2016 Georg Petzold, Eric S. Fischer, Nicolas H. Thomä
Structural basis of lenalidomide-induced CK1α degradation by the CRL4CRBN ubiquitin ligase
published pages: 127-130, ISSN: 0028-0836, DOI: 10.1038/nature16979
Nature 532/7597 2019-07-02
2017 Stefano Mattarocci, Julia K Reinert, Richard D Bunker, Gabriele A Fontana, Tianlai Shi, Dominique Klein, Simone Cavadini, Mahamadou Faty, Maksym Shyian, Lukas Hafner, David Shore, Nicolas H Thomä, Ulrich Rass
Rif1 maintains telomeres and mediates DNA repair by encasing DNA ends
published pages: 588-595, ISSN: 1545-9993, DOI: 10.1038/nsmb.3420
Nature Structural & Molecular Biology 24/7 2019-07-02
2016 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, Nicolas H. Thomä
Cullin–RING ubiquitin E3 ligase regulation by the COP9 signalosome
published pages: 598-603, ISSN: 0028-0836, DOI: 10.1038/nature17416
Nature 531/7596 2019-07-02
2018 Quinlan L. Sievers, Georg Petzold, Richard D. Bunker, Aline Renneville, Mikołaj Słabicki, Brian J. Liddicoat, Wassim Abdulrahman, Tarjei Mikkelsen, Benjamin L. Ebert, Nicolas H. Thomä
Defining the human C2H2 zinc finger degrome targeted by thalidomide analogs through CRBN
published pages: eaat0572, ISSN: 0036-8075, DOI: 10.1126/science.aat0572
Science 362/6414 2019-03-27

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