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

John T Petroff 2nd; 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; Wayland W L Cheng

doi:10.1038/s41467-022-34813-5

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

Nat Commun. 2022 Nov 17;13(1):7017. doi: 10.1038/s41467-022-34813-5.

Authors

John T Petroff 2nd¹, Noah M Dietzen¹, Ezry Santiago-McRae², Brett Deng¹, Maya S Washington¹, Lawrence J Chen¹, K Trent Moreland¹, Zengqin Deng^{3

4}, Michael Rau⁵, James A J Fitzpatrick^{3

5

6

7}, Peng Yuan^{3

4}, Thomas T Joseph⁸, Jérôme Hénin⁹, Grace Brannigan^{2

10}, Wayland W L Cheng¹¹

Affiliations

¹ Department of Anesthesiology, Washington University School of Medicine, Saint Louis, MO, USA.
² Center for Computational and Integrative Biology, Rutgers University, Camden, NJ, USA.
³ Department of Cell Biology and Physiology, Washington University School of Medicine, Saint Louis, MO, USA.
⁴ Center for the Investigation of Membrane Excitability Diseases, Washington University School of Medicine, Saint Louis, MO, USA.
⁵ Center for Cellular Imaging, Washington University School of Medicine, Saint Louis, MO, USA.
⁶ Department of Neuroscience, Washington University School of Medicine, Saint Louis, MO, USA.
⁷ Department of Biomedical Engineering, Washington University School of Medicine, Saint Louis, MO, USA.
⁸ Department of Anesthesiology and Critical Care, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁹ Laboratoire de Biochimie Théorique, Institut de Biologie Physico-Chimique, Université Paris Cité, CNRS UPR 9080, Paris, France.
¹⁰ Department of Physics, Rutgers University, Camden, NJ, USA.
¹¹ Department of Anesthesiology, Washington University School of Medicine, Saint Louis, MO, USA. wayland.cheng@wustl.edu.

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.

Publication types

Research Support, U.S. Gov't, Non-P.H.S.
Research Support, N.I.H., Extramural

MeSH terms

Binding Sites
Ligand-Gated Ion Channels* / chemistry
Ligand-Gated Ion Channels* / metabolism
Liposomes
Phosphatidylglycerols
Phospholipids

Substances

Ligand-Gated Ion Channels
Phospholipids
Phosphatidylglycerols
Liposomes

Abstract

Publication types

MeSH terms

Substances

Grants and funding