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Structural characterization of a Kir potassium channel and its involvement in Andersen’s syndrome

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 Andersen’s syndrome (AS), Bartter’s 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.

Coordinator

SORBONNE UNIVERSITE
Net EU contribution
€ 196 707,84
Address
21 RUE DE L'ECOLE DE MEDECINE
75006 Paris
France

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Region
Ile-de-France Ile-de-France Paris
Activity type
Higher or Secondary Education Establishments
Links
Total cost
€ 196 707,84