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Regulation and Function of Cullin-Ring E3 ubiquitin ligases and the Nedd8 ubiquitin-like protein modification system

Objective

Cullin-RING E3 ubiquitin ligases (CRLs) are multi-subunit enzyme complexes that catalyze isopeptide bond formation between the C-terminal glycine residue of the small protein ubiquitin and lysine residues of substrate proteins (ubiquitination). Multiple rounds of ubiquitination lead to the formation of ubiquitin chains, which are recognized by the 26S-proteasome, a protease that degrades the substrates. Targeted protein degradation by CRLs is an important part of many essential cellular processes. Progression of the cell cycle, for example, requires CRL-dependent ubiquitination and degradation of cyclin-dependent kinase inhibitors (CKIs). Clearly, substrate ubiquitination needs to occur at the right time and place, and it is thus essential that CRL activity is tightly regulated. In fact, the malfunction of CRLs has been associated with many human diseases, including cancer. One mode of CRL regulation is the activation of the ligase by the small ubiquitin-like molecule Nedd8 (neddylation). Neddylation of the cullin triggers the formation of an active ligase complex and induces structural changes that allow efficient substrate ubiquitination. My proposal aims at gaining mechanistic insights into the activation and inactivation cycles of CRL complexes. I propose to study the regulation of cullin neddylation and the role of the newly identified Nedd8 E3 ligase Dcn1 in this process. I will identify new substrates of the Nedd8 pathway with yeast genetics and biochemistry and generate a systems-wide map of genetic interactions with CRL substrates and regulators using synthetic genetic array (SGA) analysis.

Field of science

  • /natural sciences/biological sciences/genetics and heredity
  • /natural sciences/biological sciences/biochemistry/biomolecules/proteins
  • /natural sciences/biological sciences/biochemistry
  • /medical and health sciences/clinical medicine/oncology/cancer
  • /natural sciences/biological sciences/biochemistry/biomolecules/proteins/enzymes

Call for proposal

ERC-2009-StG
See other projects for this call

Funding Scheme

ERC-SG - ERC Starting Grant

Host institution

UNIVERSITY OF DUNDEE
Address
Nethergate
DD1 4HN Dundee
United Kingdom
Activity type
Higher or Secondary Education Establishments
EU contribution
€ 1 397 676,60
Principal investigator
Thimo Kasimir Kurz (Dr.)
Administrative Contact
Kathryn Williamson (Dr.)

Beneficiaries (1)

UNIVERSITY OF DUNDEE
United Kingdom
EU contribution
€ 1 397 676,60
Address
Nethergate
DD1 4HN Dundee
Activity type
Higher or Secondary Education Establishments
Principal investigator
Thimo Kasimir Kurz (Dr.)
Administrative Contact
Kathryn Williamson (Dr.)