Regulation of a pentameric ligand-gated ion channel by a semiconserved cationic lipid-binding site.
Cys-loop receptor
ELIC
electrophysiology
molecular dynamics
pentameric ligand-gated ion channel
site-directed mutagenesis
Journal
The Journal of biological chemistry
ISSN: 1083-351X
Titre abrégé: J Biol Chem
Pays: United States
ID NLM: 2985121R
Informations de publication
Date de publication:
08 2021
08 2021
Historique:
received:
23
03
2021
revised:
10
06
2021
accepted:
18
06
2021
pubmed:
23
6
2021
medline:
15
12
2021
entrez:
22
6
2021
Statut:
ppublish
Résumé
Pentameric ligand-gated ion channels (pLGICs) are crucial mediators of electrochemical signal transduction in various organisms from bacteria to humans. Lipids play an important role in regulating pLGIC function, yet the structural bases for specific pLGIC-lipid interactions remain poorly understood. The bacterial channel ELIC recapitulates several properties of eukaryotic pLGICs, including activation by the neurotransmitter GABA and binding and modulation by lipids, offering a simplified model system for structure-function relationship studies. In this study, functional effects of noncanonical amino acid substitution of a potential lipid-interacting residue (W206) at the top of the M1-helix, combined with detergent interactions observed in recent X-ray structures, are consistent with this region being the location of a lipid-binding site on the outward face of the ELIC transmembrane domain. Coarse-grained and atomistic molecular dynamics simulations revealed preferential binding of lipids containing a positive charge, particularly involving interactions with residue W206, consistent with cation-π binding. Polar contacts from other regions of the protein, particularly M3 residue Q264, further support lipid binding via headgroup ester linkages. Aromatic residues were identified at analogous sites in a handful of eukaryotic family members, including the human GABA
Identifiants
pubmed: 34157288
pii: S0021-9258(21)00699-2
doi: 10.1016/j.jbc.2021.100899
pmc: PMC8327344
pii:
doi:
Substances chimiques
Cations
0
Ligand-Gated Ion Channels
0
Lipids
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
100899Subventions
Organisme : Medical Research Council
ID : MR/L021676/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/L021676
Pays : United Kingdom
Informations de copyright
Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Conflict of interest The authors declare no conflict of interest.
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