Title | A lipid site shapes the agonist response of a pentameric ligand-gated ion channel. |
Publication Type | Journal Article |
Year of Publication | 2019 |
Authors | Hénault, C. M., C. Govaerts, R. Spurny, M. Brams, A. Estrada-Mondragon, J. Lynch, D. Bertrand, E. Pardon, G. L. Evans, K. Woods, B. W. Elberson, L. G. Cuello, G. Brannigan, H. Nury, J. Steyaert, J. E. Baenziger, and C. Ulens |
Journal | Nat Chem Biol |
Volume | 15 |
Issue | 12 |
Pagination | 1156-1164 |
Date Published | 2019 Dec |
ISSN | 1552-4469 |
Abstract | 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 GABA 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. |
DOI | 10.1038/s41589-019-0369-4 |
Alternate Journal | Nat. Chem. Biol. |
PubMed ID | 31591563 |
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