Project description
Insight into enzymes that erase post-translational modifications
Post-translational modifications (PTMs) regulate protein activity, stability and interactions through the addition of chemical groups. These modifications are dynamically removed by enzymes known as erasers, which have become promising drug targets. However, studying erasers is challenging due to their ability to recognise multiples substrates. The ERC-funded CHEMTUBIO project introduces an innovative method for detecting eraser activity in situ directly on protein complexes. This approach will be applied to enzymes that remove PTMs from tubulin, a key structural component of the cytoskeleton. Understanding how these enzymes function could reveal new therapeutic avenues for cardiac, neuronal and muscular disorders linked to disrupted tubulin regulation.
Objective
Erasers of protein post-translational modifications are ubiquitous regulatory enzymes that control cellular function and are targeted for the treatment of disease. One key example are erasers of histone acetylation, where inhibitors have reached the clinic as cancer chemotherapy. Currently, however, multiple other erasers lack tools of study to determine their relevance and generate clinical candidate molecules. One main reason for this limitation is that erasers display multivalent substrate recognition mechanisms that are difficult to replicate with standard assays in vitro and can jeopardise data translation. I have recently developed a solution to detect histone deacetylase activity in situ not on peptides, as it commonly done, but on semi-synthetic protein substrates and complexes, and still applicable to in vitro screening. My preliminary data supports that this methodology can be applied as a more general strategy, enabling studies and drug development on erasers currently inaccessible. Moreover, it holds great potential to localise eraser activity in living systems and generate maps of enzyme action on endogenous biological structures. CHEMTUBIO aims to generalise in situ eraser activity detection through application to the erasers of tubulin tail detyrosination. These enzymes generate gradients of detyrosination across the cytoskeleton lattice through mechanisms unknown and, even though inhibitors are attractive to treat cardiac and neuronal disorders, no probes are available for further investigation. Here, we will address these knowledge gaps and provide in situ sensors and chemical probes to advance the therapeutic application of detyrosinase inhibition. Furthermore, CHEMTUBIO will develop semi-synthesis methods to allow the study of microtubule lumen modifications. Erasers of luminal acetylation are attractive targets against neuromuscular disease and cancer, and we will provide key mechanistic knowledge to boost future therapeutic developments.
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.
- engineering and technology electrical engineering, electronic engineering, information engineering electronic engineering sensors
- medical and health sciences clinical medicine oncology
- natural sciences biological sciences biochemistry biomolecules proteins enzymes
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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)
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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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Call for proposal
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(opens in new window) ERC-2025-STG
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08028 Barcelona
Spain
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