Regulation of a pentameric ligand-gated ion channel by a semiconserved cationic lipid-binding site
| Autor: | Marijke Brams, Diletta Pasini, Akshay Sridhar, Chris Ulens, Sarah C. R. Lummis, Kumiko Kambara, Rebecca J. Howard, Aujan Mehregan, Erik Lindahl, Daniel Bertrand |
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| Přispěvatelé: | Lummis, Sarah [0000-0001-9410-9805], Apollo - University of Cambridge Repository |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
DYNAMICS
MECHANISM 0301 basic medicine Models Molecular POPG palmitoyloleoylphosphatidylglycerol TMD transmembrane domain DOTAP dipalmitoyl-3-trimethylammonium-propane PG phosphatidylglycerol Crystallography X-Ray Biochemistry ACTIVATION chemistry.chemical_compound PC phosphatidylcholine Xenopus laevis Chemistry GABAA receptor Editors' Pick Lipids Transmembrane domain VSD voltage-sensor domain K+ CHANNEL Ligand-gated ion channel Protein Structural Elements Signal transduction site-directed mutagenesis Life Sciences & Biomedicine Research Article Protein Binding STRUCTURAL BASIS Biochemistry & Molecular Biology SOFTWARE NEWS Protein subunit ICD intracellular domain Cys-loop receptor POPC palmitoyloleoylphosphatidylcholine PE phosphatidylethanolamine Cell Line 03 medical and health sciences pLGIC pentameric ligand-gated ion channel Cations Animals Humans Molecular Biology POPC Ion channel G protein-coupled receptor GPCR G-protein-coupled receptor Science & Technology RECEPTOR 030102 biochemistry & molecular biology RMSD root-mean-squared deviation Cell Biology Ligand-Gated Ion Channels electrophysiology nAChR nicotinic acetylcholine receptor ECD extracellular domain WT wild-type molecular dynamics PROTEIN INTERACTIONS 030104 developmental biology GENERAL-ANESTHETICS Biophysics Oocytes ELIC pentameric ligand-gated ion channel X-RAY-STRUCTURE |
| Zdroj: | The Journal of Biological Chemistry Journal of Biological Chemistry |
| ISSN: | 1083-351X 0021-9258 |
| Popis: | 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 GABAA receptor ε subunit, suggesting conservation of relevant interactions in other evolutionary branches. Further mutagenesis experiments indicated that mutations at this site in ε-containing GABAA receptors can change the apparent affinity of the agonist response to GABA, suggesting a potential role of this site in channel gating. In conclusion, this work details type-specific lipid interactions, which adds to our growing understanding of how lipids modulate pLGICs. ispartof: JOURNAL OF BIOLOGICAL CHEMISTRY vol:297 issue:2 ispartof: location:United States status: published |
| Databáze: | OpenAIRE |
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