Affiliation:
1. Science for Life Laboratory & Swedish e-Science Research Center, Department of Applied Physics, KTH Royal Institute of Technology
2. Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University
Abstract
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.
Funder
Knut och Alice Wallenbergs Stiftelse
Vetenskapsrådet
Sven och Lilly Lawskis Fond för Naturvetenskaplig Forskning
Swedish e-Science Research Centre
European Commission
Subject
General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience