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

Project description

Unveiling the molecular mechanisms of ubiquitination

The ubiquitin system is a highly regulated and intricate cellular pathway responsible for protein degradation by the proteasome. It involves the attachment of a small protein called ubiquitin to target proteins by specific ubiquitin E3 ligase enzymes. The ubiquitin transfer system has emerged as an attractive drug target for intervening on specific disease-associated proteins. Funded by the European Research Council, the CsnCRL project aims to elucidate the molecular mechanisms responsible for the regulation of the ubiquitination process and especially the E3 ligases. Researchers will undertake advanced structural and functional studies using techniques like X-ray crystallography and cryo-electron microscopy. Apart from fundamental insight into ubiquitination, project results will help decode the behaviour of multi-subunit complexes.

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.

Host institution

FRIEDRICH MIESCHER INSTITUTE FOR BIOMEDICAL RESEARCH FONDATION
Net EU contribution
€ 2 200 677,00
Address
MAULBEERSTRASSE 66
4058 Basel
Switzerland

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Region
Schweiz/Suisse/Svizzera Nordwestschweiz Basel-Stadt
Activity type
Research Organisations
Links
Total cost
€ 2 200 677,00

Beneficiaries (1)