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Elife. 2019 Nov 14;8. pii: e50766. doi: 10.7554/eLife.50766.

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

Author information

1
Department of Anesthesiology, Washington University, Saint Louis, United States.
2
Department of Internal Medicine, Mass Spectrometry Resource, Division of Endocrinology, Diabetes, Metabolism, and Lipid Research, Washington University, Saint Louis, United States.
3
Department of Anesthesiology, Weill Cornell Medical College, New York, United States.
4
Center for Computational and Integrative Biology, Rutgers University, Camden, United States.
5
Department of Physics, Rutgers University, Camden, United States.

Abstract

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.

KEYWORDS:

desensitization; mass spectrometry; membrane channels; molecular biophysics; none; phospholipids; structural biology

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