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

Author

Listed:
  • 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
    Washington University School of Medicine)

  • Michael Rau

    (Washington University School of Medicine)

  • James A. J. Fitzpatrick

    (Washington University School of Medicine
    Washington University School of Medicine
    Washington University School of Medicine
    Washington University School of Medicine)

  • Peng Yuan

    (Washington University School of Medicine
    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
    Rutgers University)

  • Wayland W. L. Cheng

    (Washington University School of Medicine)

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.

Suggested Citation

  • 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 & Th, 2022. "Open-channel structure of a pentameric ligand-gated ion channel reveals a mechanism of leaflet-specific phospholipid modulation," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34813-5
    DOI: 10.1038/s41467-022-34813-5
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    References listed on IDEAS

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    Cited by:

    1. Nikhil Bharambe & Zhuowen Li & David Seiferth & Asha Manikkoth Balakrishna & Philip C. Biggin & Sandip Basak, 2024. "Cryo-EM structures of prokaryotic ligand-gated ion channel GLIC provide insights into gating in a lipid environment," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    2. T. Bertie Ansell & Wanling Song & Claire E. Coupland & Loic Carrique & Robin A. Corey & Anna L. Duncan & C. Keith Cassidy & Maxwell M. G. Geurts & Tim Rasmussen & Andrew B. Ward & Christian Siebold & , 2023. "LipIDens: simulation assisted interpretation of lipid densities in cryo-EM structures of membrane proteins," Nature Communications, Nature, vol. 14(1), pages 1-14, December.

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