Project description
Specificity for protein degradation in the ubiquitin system
Selective protein degradation via the ubiquitin-proteasome system (UPS) plays an important role in many cellular processes. The principal specificity determinants are E3 ubiquitin ligases, which recognise cognate degron motifs found in substrate proteins. However, for the majority of E3 ligases encoded in the human genome, little is known about how they recognise their substrates. Using an expression screening platform to perform proteome-wide stability profiling, the ERC-funded E3-SUBSTRATES project aims to address this bottleneck. It will first systematically interrogate the proteome to identify relevant E3 ligase substrates, followed by detailed mechanistic investigation of their mode of degradation. The findings on how specificity is attained in the UPS could open the door to future development of small molecule therapies.
Objective
As the primary route through which eukaryotic cells achieve selective protein degradation, the ubiquitin-proteasome system (UPS) plays a key role in virtually all critical cellular processes. A major unresolved question concerns how the ubiquitin system attains such high selectivity towards its myriad of substrates. The main specificity determinants are the E3 ubiquitin ligases, which recognise cognate ‘degron’ motifs found in substrate proteins. However, for the majority of the ~600 E3 ligases encoded in the human genome we still have little or no knowledge as to their substrates, and our understanding of degron motifs remains limited. This knowledge gap prevents us from appreciating how key cellular processes are regulated and impedes the development of small molecules capable of either inhibiting or hijacking E3 ligases for therapeutic benefit.
To complement the biochemical and proteomic techniques that have served as the primary route to discovery in the field, we seek to exploit functional genetic approaches to understand how E3 ligases recognise their substrates. Leveraging an expression screening platform that enables proteome-wide stability profiling, our specific goals are to: (1) identify physiological substrates regulated via degrons lying at their extreme C-termini, (2) define novel mechanisms through which conditional protein degradation is achieved via phospho-degrons, and (3) characterise the spectrum of degradative pathways responsible for the instability of hundreds of the most short-lived cellular proteins. For each goal, we will first provide global insight by systematically interrogating the proteome for relevant substrates; for the most interesting candidates, we will then seek detailed mechanistic understanding to illuminate new biology. Successful completion of this work will transform our understanding of how specificity is achieved within the UPS and greatly facilitate its future therapeutic manipulation.
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 biological sciences genetics genomes
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Keywords
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
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Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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HORIZON.1.1 - European Research Council (ERC)
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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.
HORIZON-ERC - HORIZON ERC Grants
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(opens in new window) ERC-2024-STG
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CB2 1TN CAMBRIDGE
United Kingdom
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