Project description
Insight into the mechanisms of cell membrane tension maintenance
The cell membrane has a central role in maintaining cellular homeostasis by controlling molecule transfer and membrane tension. Accumulating evidence indicates a role for the target of rapamycin complex 2 (TORC2) pathway, while the palmitoylcarnitine (PalmC) inhibitor seems to reversibly impact membrane tension. Scientists of the EU-funded MEMTOR project will work to understand the PalmC mode of action and identify the transporter responsible for its uptake. Using a variety of methodological approaches, scientists will unveil key proteins implicated in the process and provide important insight into the therapeutic potential of PalmC.
Objective
Maintenance of membrane tension at the plasma membrane (PM) is an important yet understudied aspect of cellular homeostasis. Dysregulated membrane tension homeostasis has roles in cancer, neurodegeneration, and metabolic syndrome but its study has been limited by a lack of tools to measure and manipulate it. The Target of Rapamycin Complex 2 (TORC2), an important signaling hub regulating cell growth, has an unexpected role in maintaining PM tension homeostasis. A screen for TORC2-specific inhibitors identified the lipophilic molecule palmitoylcarnitine (PalmC) which induces a reversible loss in PM tension. It is currently unknown how PalmC is able to induce this tension loss, but understanding both its mode-of-action and how cells are able to recover from its effects are important for its development as a potential membrane-targeting drug. In this proposal, we aim to reveal key proteins involved in the effects of PalmC (Aim 1). We expect that a specific plasma membrane-localized transporter will mediate its uptake. Both by identifying this protein and solving its structure in a native-like lipidic environment and/or in complex with PalmC, we hope to reveal new insights into how PalmC might be tailored for therapeutic potential. We will also investigate the recovery process post-PalmC treatment, starting from the observation that the TORC2-activating protein Slm1 co-localizes with TORC2 and forms very large clusters at sites of PalmC-induced membrane invaginations (Aim 2). Previous observations of TORC1 regulation suggest that clustering is correlated with the formation of ordered polymers. To investigate whether this is a conserved mechanism of regulation, we will attempt to isolate a Slm1-TORC2 superstructure and determine its structure using cryoEM with the expectation that structural details about the interactions between these proteins within the superstructure will reveal mechanistic insights into the regulation of TORC2, as well as membrane tension.
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 neurobiology
- natural sciences biological sciences biochemistry biomolecules proteins
- natural sciences biological sciences cell biology
- natural sciences chemical sciences polymer sciences
- medical and health sciences basic medicine physiology homeostasis
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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.
1211 Geneve
Switzerland
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.