Project description
Mechanistic insight into post-translational modifications of proteins
Protein function, stability and interaction with other proteins is often regulated by post-translational modifications. Ubiquitination is a post-translational modification process that involves the covalent attachment of ubiquitin molecules to target proteins by enzymes called E3 ubiquitin ligases. Ubiquitination plays a crucial role in maintaining protein homeostasis by facilitating the efficient elimination of damaged or unnecessary proteins. Funded by the European Research Council, the RINGE3 project aims to investigate how RING E3 enzymes interact with other ubiquitin-conjugating enzymes (E2) and substrates, and how they are regulated. The results will help us better understand the mechanisms of RING E3-mediated ubiquitination and may lead to new therapies for diseases such as cancer.
Objective
Ubiquitin (Ub) conjugation regulates a myriad of cellular processes in the eukaryotic cell. Ub-ligases (E3) play a pivotal role in deciding the substrate’s fate and function by catalyzing the transfer of Ub from Ub-conjugating enzyme (E2) to a substrate protein lysine sidechain. Successive rounds of E3-catalyzed substrate ubiquitination lead to the formation of poly-Ub chains or multi-monoubiquitination, which direct the substrate to different biological fates such as degradation by the 26S proteasome. RING E3s comprise the largest family of E3s with approximately 600 members in humans. Over the last fifteen years, structural biology and biochemical studies have paved the way for understanding how RING E3s interact with E2s and substrates, and how they are regulated. Recently my group has trapped the crystal structure of a RING E3 bound to an E2 covalently-linked to Ub (E2~Ub), thus providing a molecular snapshot of how RING E3 optimizes E2~Ub for catalysis. Despite these advances, the mechanisms of RING E3-catalyzed ubiquitination are not completely understood. Here, we propose to investigate three key aspects of RING E3 functions. First, we will determine structures of several RING E3s bound to E2~Ub to dissect the molecular basis for RING E3-E2~Ub selectivity. Second, our recent structure of a RING E3, Cbl-b, bound to E2~Ub and a substrate peptide provides a starting point for structural determination of a more challenging RING E3-E2~Ub-intact substrate complex to elucidate the mechanisms of substrate ubiquitination. Third, we have developed an ubiquitinated Cbl-substrate mimetic to study the mechanisms of RING E3-catalyzed poly-ubiquitination using structural and biochemical approaches. Expected results will greatly expand our knowledge of RING E3-mediated ubiquitination and will foster strategies in exploiting E3s for therapeutic development, since deregulation of E3s underlies many diseases including cancers.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- natural sciences biological sciences biochemistry biomolecules proteins proteomics
- natural sciences chemical sciences catalysis
- natural sciences chemical sciences organic chemistry amines
- natural sciences biological sciences biochemistry biomolecules proteins enzymes
- natural sciences biological sciences molecular biology structural biology
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Programme(s)
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC)
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Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
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Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
ERC-COG - Consolidator Grant
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Call for proposal
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Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
(opens in new window) ERC-2014-CoG
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G61 1BD Bearsden
United Kingdom
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