Project description
Insight into ubiquitin ligase specificity
Ubiquitination is a post-translational modification where the small protein ubiquitin is covalently attached to a substrate protein, targeting it for degradation in the proteasome. E3 ligase enzymes select the proteins to be modified and add ubiquitin chains. Although deregulation of this process has been associated with many human diseases, the precise mechanisms governing ligase specificity are not well understood. With the support of the Marie Skłodowska-Curie Actions programme, the USefUL project aims to address this gap by investigating the E3 ligase HACE1 that is known for its tumour-suppressing and neurodevelopmental regulating role. The goal is to identify the substrates of HACE1 and help understand ubiquitin ligase specificities.
Objective
Ubiquitination is a pivotal regulator of eukaryotic protein functions, governing myriad cellular pathways. Its deregulation causes manifold human diseases, yet our incomplete understanding of the underlying structural mechanisms has limited therapeutic efforts. Within the ubiquitination machinery, ubiquitin ligases (E3s) present major specificity determinants, as they select substrates for modification and decorate them with ubiquitin signals. These signals frequently comprise ubiquitin chains of various linkage types, each associated with distinct functional outcomes for the modified substrate. To understand how ubiquitin ligases select and modify substrates with specificity is, therefore, pivotal to understand and efficiently manipulate the ubiquitin system.
To address this key question, my project focuses on the human HECT-type E3 HACE1, an important, yet poorly characterized neurodevelopmental regulator and tumour suppressor. I will structurally recapitulate linkage-specific ubiquitin chain formation by HACE1 on its physiological substrate RAC1 by cryo-EM, complemented by structure-guided mutagenesis and functional analyses in vitro and in cells. Moreover, I will develop new technologies to identify HACE1 substrates in cells, using tailored, mechanism-based crosslinking strategies. Capitalizing on my expertise in unnatural amino acid incorporation, I will insert a photoactivatable lysine-reactive amino acid at the E3 active site for covalently capturing of substrates based on proximity, followed by their mass spectrometry-based identification. This strategy may later be adapted to other cysteine-reactive E3 classes.
Taken together, my studies will advance our fundamental understanding of ubiquitin ligase specificities in a disease-relevant model system, while establishing innovative new tools for substrate identification in the ubiquitin system.
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
- natural sciences chemical sciences organic chemistry amines
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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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HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA)
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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.
Funding Scheme
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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-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European Fellowships
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Call for proposal
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(opens in new window) HORIZON-MSCA-2025-PF
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80539 MUNCHEN
Germany
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