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

John T. Petroff, Noah M. Dietzen, Ezry Santiago-McRae, Brett Deng, Maya S. Washington, Lawrence J. Chen, K. Trent Moreland, Zengqin Deng, Michael Rau, James A. J. Fitzpatrick, Peng Yuan, Thomas T. Joseph, Jérôme Hénin, Grace Brannigan and Wayland W. L. Cheng ()
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John T. Petroff: Washington University School of Medicine
Noah M. Dietzen: Washington University School of Medicine
Ezry Santiago-McRae: Rutgers University
Brett Deng: Washington University School of Medicine
Maya S. Washington: Washington University School of Medicine
Lawrence J. Chen: Washington University School of Medicine
K. Trent Moreland: Washington University School of Medicine
Zengqin Deng: Washington University School of Medicine
Michael Rau: Washington University School of Medicine
James A. J. Fitzpatrick: Washington University School of Medicine
Peng Yuan: Washington University School of Medicine
Thomas T. Joseph: University of Pennsylvania
Jérôme Hénin: Institut de Biologie Physico-Chimique, Université Paris Cité, CNRS UPR 9080
Grace Brannigan: Rutgers University
Wayland W. L. Cheng: Washington University School of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-34813-5

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