Project description
Characterisation of the structure and molecular mechanisms of Kir channels in relation to Andersen's syndrome
Inward-rectifier potassium (Kir) channels are integral membrane proteins that control the K+ ion current in cell membranes, with phosphatidylinositol 4,5-bisphosphate (PIP2) being an essential regulator of the activity in eukaryotes. Genetically inherited defects in the Kir channels are linked to various chronic debilitating diseases such as Andersen’s syndrome (AS), for which there is no effective treatment available. Funded by the Marie Skłodowska-Curie Actions programme, the KIRPAS project aims to decipher high-resolution structures of the human Kir2.1 channel wild type and an AS-causing mutant at the PIP2 interaction site and unravel the molecular mechanisms of the channel gating both in the presence and absence of PIP2, using cryo-electron microscopy in combination with image analysis and a molecular dynamics simulations approach.
Objective
The inward rectifier potassium (Kir) channels belong to a family of integral membrane proteins that selectively control the K+ ion permeation in cell membranes. They are ubiquitously expressed throughout the human body and regulate the membrane electrical excitability and K+ transport in many cell types. The gating of Kir channels is modulated by various intracellular ligands, with phosphatidylinositol-4,5-bisphosphate (PIP2) being an essential molecule to Kir channel activity in eukaryotes. The physiological importance of the Kir channels is highlighted by the fact that genetically-inherited defects in the Kir channels are responsible for a number of human diseases, such as Andersens syndrome (AS), Bartters syndrome, and neonatal diabetes, which are often chronically debilitating and for which there are no efficient therapeutic treatments. This project goals to obtain high-resolution structures of the human Kir2.1 channel wild type (WT) and an AS-causing mutant (R312H) located at interaction site of PIP2, in the presence and absence of PIP2 as well as the description of the molecular mechanisms allowing gating of the channels in the WT and mutated forms with/without PIP2 using advanced molecular dynamics simulations techniques. For this, this project proposes the integration of cryo-microscopy (cryo-EM) combined with image analysis (single particle analysis or 2D crystallography) with a recently developed molecular dynamics simulations approach (MDeNM), which is a powerful tool to structurally characterize functional motions occurring over long time scales. The description of full gating mechanism of human Kir2.1 channel and the PIP2 role on its dynamics, as well as the understanding of the clinically-relevant disease-causing mutation impact on the structure, dynamics, and function of Kir channels can provide the structural basis for investigating potential rationally-designed therapeutic modulators for the AS treatment.
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.
- natural sciences biological sciences cell biology cell signaling
- natural sciences physical sciences optics microscopy electron microscopy
- natural sciences biological sciences biochemistry biomolecules proteins protein folding
- natural sciences biological sciences molecular biology molecular neuroscience
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.
75006 PARIS
France
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.