Project description
Mechanical effects on single proteins and protein translocation across pores
Proteins are involved in most cellular processes. Their function is modulated in part by changes in their 3D structure, which, in turn, can be modulated by mechanical forces. Studies of mechanical effects on proteins have been limited to in vitro single-molecule experiments, where effects on cell and tissue function cannot be studied. The ERC-funded ProtMechCell project aims to investigate whether the mechanical stability and local structure of proteins are a master regulator of protein translocation kinetics across pores of all types. The state-of-the-art mechanical, opto-genetic, and intracellular force spectrometry techniques will investigate protein elasticity, the movement of transcription factors and proteins across pores, and intracellular single-protein stability under pulling.
Objective
Mechanical stimuli regulate an increasingly large number of cellular and tissue functions. However, the effect that those macroscopic forces have on the underpinning proteins is poorly understood.
Most of our knowledge of protein dynamics under force is still restricted to in vitro single-molecule experiments. Collectively, these molecular measurements have revealed that, when denatured with force, proteins unfold and stretch along their end-to-end length, following a completely different pathway from that sampled in biochemical denaturation. Yet, we are still lacking fundamental understanding of how mechanical unfolding of proteins occurs in the cell, and how it impacts cellular function.
Here, we propose to develop and apply a combination of state-of-the-art mechanical techniques across scales aiming to correlate the nanomechanical properties of proteins measured in vitro with their behaviour in their physiological cellular context.
We will first study how the regulation of protein elasticity –through dynamic force-induced unfolding and refolding, protein binding and post-translational modifications in cryptic sites of key mechanosensors– affects cellular mechanotransduction. We will also examine, using single-cell optogenetic experiments, how the mechanical unfolding of mechanosensitive transcription factors regulate their import rate into the cell nucleus across the nuclear pore complex, and the potential physiological implications.
We will then test the hypothesis that the mechanical stability and local structure of proteins emerge as a general master regulator of their translocation kinetics across pores of varying sizes and functions, including those present in proteasomes, peroxisomes and lysosomes.
Finally, we will harness the natural specificity of the distinct cellular pores to inspire an intracellular force spectrometer to measure changes in the mechanical stability of a single protein under its functional pulling velocity inside the cell.
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.
This project's classification has been human-validated.
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.
This project's classification has been human-validated.
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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HORIZON.1.1 - European Research Council (ERC)
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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.
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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.
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Call for proposal
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(opens in new window) ERC-2024-ADG
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WC2R 2LS London
United Kingdom
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