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Article Dans Une Revue Nature Chemical Biology Année : 2019

A lipid site shapes the agonist response of a pentameric ligand-gated ion channel

Els Pardon
Hugues Nury
Jan Steyaert

Résumé

Phospholipids are key components of cellular membranes and are emerging as important functional regulators of different membrane proteins, including pentameric ligand-gated ion channels (pLGICs). Here, we take advantage of the prokaryote channel ELIC (Erwinia ligand-gated ion channel) as a model to understand the determinants of phospholipid interactions in this family of receptors. A high-resolution structure of ELIC in a lipid-bound state reveals a phospholipid site at the lower half of pore-forming transmembrane helices M1 and M4 and at a nearby site for neurosteroids, cholesterol or general anesthetics. This site is shaped by an M4-helix kink and a Trp-Arg-Pro triad that is highly conserved in eukaryote GABAA/C and glycine receptors. A combined approach reveals that M4 is intrinsically flexible and that M4 deletions or disruptions of the lipid-binding site accelerate desensitization in ELIC, suggesting that lipid interactions shape the agonist response. Our data offer a structural context for understanding lipid modulation in pLGICs.

Dates et versions

hal-02413036 , version 1 (16-12-2019)

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Citer

Camille Hénault, Cedric Govaerts, Radovan Spurny, Marijke Brams, Argel Estrada-Mondragon, et al.. A lipid site shapes the agonist response of a pentameric ligand-gated ion channel. Nature Chemical Biology, 2019, 15 (12), pp.1156-1164. ⟨10.1038/s41589-019-0369-4⟩. ⟨hal-02413036⟩
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