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Article Dans Une Revue Nature Communications Année : 2022

Open-channel structure of a pentameric ligand-gated ion channel reveals a mechanism of leaflet-specific phospholipid modulation

John Petroff
  • Fonction : Auteur
Noah Dietzen
  • Fonction : Auteur
Ezry Santiago-Mcrae
Brett Deng
  • Fonction : Auteur
Maya Washington
  • Fonction : Auteur
Lawrence Chen
  • Fonction : Auteur
K. Trent Moreland
Zengqin Deng
  • Fonction : Auteur
Michael Rau
James Fitzpatrick
Peng Yuan
Thomas Joseph
Wayland Cheng

Résumé

Abstract Pentameric ligand-gated ion channels (pLGICs) mediate synaptic transmission and are sensitive to their lipid environment. The mechanism of phospholipid modulation of any pLGIC is not well understood. We demonstrate that the model pLGIC, ELIC ( Erwinia ligand-gated ion channel), is positively modulated by the anionic phospholipid, phosphatidylglycerol, from the outer leaflet of the membrane. To explore the mechanism of phosphatidylglycerol modulation, we determine a structure of ELIC in an open-channel conformation. The structure shows a bound phospholipid in an outer leaflet site, and structural changes in the phospholipid binding site unique to the open-channel. In combination with streamlined alchemical free energy perturbation calculations and functional measurements in asymmetric liposomes, the data support a mechanism by which an anionic phospholipid stabilizes the activated, open-channel state of a pLGIC by specific, state-dependent binding to this site.
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Dates et versions

hal-03858898 , version 1 (05-12-2023)

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John Petroff, Noah Dietzen, Ezry Santiago-Mcrae, Brett Deng, Maya Washington, et al.. Open-channel structure of a pentameric ligand-gated ion channel reveals a mechanism of leaflet-specific phospholipid modulation. Nature Communications, 2022, 13 (1), pp.7017. ⟨10.1038/s41467-022-34813-5⟩. ⟨hal-03858898⟩
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