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

Autor: Petroff JT 2nd; Department of Anesthesiology, Washington University School of Medicine, Saint Louis, MO, USA., Dietzen NM; Department of Anesthesiology, Washington University School of Medicine, Saint Louis, MO, USA., Santiago-McRae E; Center for Computational and Integrative Biology, Rutgers University, Camden, NJ, USA., Deng B; Department of Anesthesiology, Washington University School of Medicine, Saint Louis, MO, USA., Washington MS; Department of Anesthesiology, Washington University School of Medicine, Saint Louis, MO, USA., Chen LJ; Department of Anesthesiology, Washington University School of Medicine, Saint Louis, MO, USA., Trent Moreland K; Department of Anesthesiology, Washington University School of Medicine, Saint Louis, MO, USA., Deng Z; Department of Cell Biology and Physiology, Washington University School of Medicine, Saint Louis, MO, USA.; Center for the Investigation of Membrane Excitability Diseases, Washington University School of Medicine, Saint Louis, MO, USA., Rau M; Center for Cellular Imaging, Washington University School of Medicine, Saint Louis, MO, USA., Fitzpatrick JAJ; Department of Cell Biology and Physiology, Washington University School of Medicine, Saint Louis, MO, USA.; Center for Cellular Imaging, Washington University School of Medicine, Saint Louis, MO, USA.; Department of Neuroscience, Washington University School of Medicine, Saint Louis, MO, USA.; Department of Biomedical Engineering, Washington University School of Medicine, Saint Louis, MO, USA., Yuan P; Department of Cell Biology and Physiology, Washington University School of Medicine, Saint Louis, MO, USA.; Center for the Investigation of Membrane Excitability Diseases, Washington University School of Medicine, Saint Louis, MO, USA., Joseph TT; Department of Anesthesiology and Critical Care, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Hénin J; Laboratoire de Biochimie Théorique, Institut de Biologie Physico-Chimique, Université Paris Cité, CNRS UPR 9080, Paris, France., Brannigan G; Center for Computational and Integrative Biology, Rutgers University, Camden, NJ, USA.; Department of Physics, Rutgers University, Camden, NJ, USA., Cheng WWL; Department of Anesthesiology, Washington University School of Medicine, Saint Louis, MO, USA. wayland.cheng@wustl.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2022 Nov 17; Vol. 13 (1), pp. 7017. Date of Electronic Publication: 2022 Nov 17.
DOI: 10.1038/s41467-022-34813-5
Abstrakt: 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.
(© 2022. The Author(s).)
Databáze: MEDLINE
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