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Discovery of lipid binding sites in a ligand-gated ion channel by integrating simulations and cryo-EM
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).ORCID iD: 0000-0001-5889-6899
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab). KTH Royal Institute of Technology, Sweden.ORCID iD: 0000-0003-2049-3378
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab). KTH Royal Institute of Technology, Sweden.ORCID iD: 0000-0002-2734-2794
Number of Authors: 42023 (English)In: eLIFE, E-ISSN 2050-084X, Vol. 12, article id RP86016Article in journal (Refereed) Published
Abstract [en]

Ligand-gated ion channels transduce electrochemical signals in neurons and other excitable cells. Aside from canonical ligands, phospholipids are thought to bind specifically to the transmembrane domain of several ion channels. However, structural details of such lipid contacts remain elusive, partly due to limited resolution of these regions in experimental structures. Here, we discovered multiple lipid interactions in the channel GLIC by integrating cryo-electron microscopy and large-scale molecular simulations. We identified 25 bound lipids in the GLIC closed state, a conformation where none, to our knowledge, were previously known. Three lipids were associated with each subunit in the inner leaflet, including a buried interaction disrupted in mutant simulations. In the outer leaflet, two intrasubunit sites were evident in both closed and open states, while a putative intersubunit site was preferred in open-state simulations. This work offers molecular details of GLIC-lipid contacts particularly in the ill-characterized closed state, testable hypotheses for state-dependent binding, and a multidisciplinary strategy for modeling protein-lipid interactions.

Place, publisher, year, edition, pages
2023. Vol. 12, article id RP86016
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Biophysics Structural Biology
Identifiers
URN: urn:nbn:se:su:diva-226504DOI: 10.7554/eLife.86016ISI: 001154973600001PubMedID: 38289224Scopus ID: 2-s2.0-85184345538OAI: oai:DiVA.org:su-226504DiVA, id: diva2:1838727
Available from: 2024-02-19 Created: 2024-02-19 Last updated: 2024-02-19Bibliographically approved

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Rovšnik, UrškaHoward, Rebecca J.Lindahl, Erik

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