Project description
Cellular homeostasis and E3 ubiquitin ligase substrate selection
Weak and transient protein–protein interactions are essential for cellular homeostasis and often involve globular domains that recognise a short linear motif in disordered regions of interacting proteins. E3 ubiquitin ligases use these interactions to recognise their substrates and the conjugation of ubiquitin chains to substrate signals for degradation by the proteasome. Many E3 ubiquitin ligases have key roles in promoting DNA damage signalling and repair pathways, providing protection from severe diseases such as cancer. The EU-funded DDRDegronDiscovery project aims to use a highly sensitive novel protein–protein interaction mapping technique, SPARK2, to identify peptides derived from the disordered proteome based on their interactions with E3 ubiquitin ligases, providing unprecedented insight into genome stability maintenance.
Objective
Weak and transient protein-protein interactions are essential for cellular homeostasis but are challenging to study and therefore incompletely understood. Many of these interactions involve globular domains that recognize a short linear motif (SLiM) in disordered regions of interacting proteins. E3 ubiquitin ligases frequently use this principle of interaction to recognize their substrates. The conjugation of ubiquitin chains to a substrate often serves as a signal for degradation by the proteasome, and the recognized SLiM is therefore referred to as a degron. The ubiquitin system has a well-established critical function in genome stability maintenance, which is of fundamental importance for avoiding severe diseases such as cancer. A number of E3 ubiquitin ligases have key roles in promoting DNA damage signaling and repair pathways, but mechanistic insights into how these ubiquitin ligases recognize their substrates are lacking. This is due in large part to an absence of sensitive methods for discovery and characterization of transient E3 ligase-degron interactions. Here, I propose to apply and combine two novel methods in an innovative workflow to remedy this knowledge gap. I will use a powerful and highly sensitive novel protein-protein interaction mapping technique (SPARK2) to screen peptides derived from the disordered proteome for their interaction with E3 ligases important for genome stability maintenance. Detailed characterization of identified potential SLiMs interacting with DNA damage-responsive E3 ligases will subsequently be performed using MRBLE:pep, a novel multiplexing approach to simultaneously quantify dozens of protein-peptide affinities that I recently helped to develop. This in-depth characterization of E3 ligase degrons, together with functional studies of validated novel E3 ligase-substrate interactions, will enable unprecedented mechanistic insights into regulatory networks underlying genome stability maintenance.
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 DNA
- natural sciences biological sciences biochemistry biomolecules proteins protein folding
- 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)
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.1.3. - EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions
MAIN PROGRAMME
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H2020-EU.1.3.2. - Nurturing excellence by means of cross-border and cross-sector mobility
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Topic(s)
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.
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.
Funding Scheme
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.
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.
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)
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Call for proposal
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
(opens in new window) H2020-MSCA-IF-2020
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Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.
1165 KOBENHAVN
Denmark
The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.