Direct binding of phosphatidylglycerol at specific sites modulates desensitization of a ligand-gated ion channel

Ailing Tong; John T Petroff, 2nd; Fong-Fu Hsu; Philipp Am Schmidpeter; Crina M Nimigean; Liam Sharp; Grace Brannigan; Wayland Wl Cheng

doi:10.7554/eLife.50766

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Direct binding of phosphatidylglycerol at specific sites modulates desensitization of a ligand-gated ion channel

Journal article

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Direct binding of phosphatidylglycerol at specific sites modulates desensitization of a ligand-gated ion channel

Ailing Tong, John T Petroff, 2nd, Fong-Fu Hsu, Philipp Am Schmidpeter, Crina M Nimigean, Liam Sharp, Grace Brannigan and Wayland Wl Cheng

eLife, Vol.8

11/14/2019

DOI: https://doi.org/10.7554/eLife.50766

PMCID: PMC6855808

PMID: 31724949

Abstract

Allosteric Regulation

DNA Mutational Analysis

Ligand-Gated Ion Channels - chemistry

Ligand-Gated Ion Channels - genetics

Ligand-Gated Ion Channels - metabolism

Mass Spectrometry

Molecular Dynamics Simulation

Phosphatidylglycerols - metabolism

Protein Binding

Protein Conformation

Synaptic Transmission

Pentameric ligand-gated ion channels (pLGICs) are essential determinants of synaptic transmission, and are modulated by specific lipids including anionic phospholipids. The exact modulatory effect of anionic phospholipids in pLGICs and the mechanism of this effect are not well understood. Using native mass spectrometry, coarse-grained molecular dynamics simulations and functional assays, we show that the anionic phospholipid, 1-palmitoyl-2-oleoyl phosphatidylglycerol (POPG), preferentially binds to and stabilizes the pLGIC, Erwinia ligand-gated ion channel (ELIC), and decreases ELIC desensitization. Mutations of five arginines located in the interfacial regions of the transmembrane domain (TMD) reduce POPG binding, and a subset of these mutations increase ELIC desensitization. In contrast, a mutation that decreases ELIC desensitization, increases POPG binding. The results support a mechanism by which POPG stabilizes the open state of ELIC relative to the desensitized state by direct binding at specific sites.

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Title: Direct binding of phosphatidylglycerol at specific sites modulates desensitization of a ligand-gated ion channel
Creators: Ailing Tong - Department of Anesthesiology, Washington University, Saint Louis, United States
John T Petroff, 2nd - Department of Anesthesiology, Washington University, Saint Louis, United States
Fong-Fu Hsu - Department of Internal Medicine, Mass Spectrometry Resource, Division of Endocrinology, Diabetes, Metabolism, and Lipid Research, Washington University, Saint Louis, United States
Philipp Am Schmidpeter - Department of Anesthesiology, Weill Cornell Medical College, New York, United States
Crina M Nimigean - Department of Anesthesiology, Weill Cornell Medical College, New York, United States
Liam Sharp - Center for Computational and Integrative Biology, Rutgers University, Camden, United States
Grace Brannigan - Department of Physics, Rutgers University, Camden, United States
Wayland Wl Cheng - Department of Anesthesiology, Washington University, Saint Louis, United States
Publication Details: eLife, Vol.8
Date published: 11/14/2019
Grant note: P30DK020579 / NIDDK NIH HHS K08 GM126336 / NIGMS NIH HHS K08GM126336 / NIGMS NIH HHS P41GM103422 / NIGMS NIH HHS P30 DK020579 / NIDDK NIH HHS R01GM124451 / NIGMS NIH HHS 18POST33960309 / American Heart Association-American Stroke Association R01 GM124451 / NIGMS NIH HHS 18POST33960309 / American Heart Association Pilot Research Grant / Center for the Investigation of Membrane Excitability Diseases
Academic Unit: Biology (FASC); Physics (FASC)
Language: English
Resource Type: Journal article
Identifiers: 991031665480104646