Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
J Biol Chem
2021 Aug 01;2972:100899. doi: 10.1016/j.jbc.2021.100899.
Show Gene links
Show Anatomy links
Regulation of a pentameric ligand-gated ion channel by a semiconserved cationic lipid-binding site.
Sridhar A
,
Lummis SCR
,
Pasini D
,
Mehregan A
,
Brams M
,
Kambara K
,
Bertrand D
,
Lindahl E
,
Howard RJ
,
Ulens C
.
???displayArticle.abstract???
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.
Figure 7. Functional characterization of the epsilon-F260E mutant in Xenopus oocytes. A and B, representative current traces evoked from Xenopus oocytes expressing the wild-type human α1β2ε GABAAR (A) and the α1β2 εF260E mutant (B). Agonist-evoked currents were obtained by application of the GABA concentrations as indicated. C, concentration–response relationships for the experiments indicated in A and B. GABA EC50-values were 2.27 ± 0.60 (n = 6, wild type) and 6.52 ± 1.80 (n = 12, ε F260E). An unpaired, two-tailed t test with Welch’s correction gave a p-value of <2.5 × 10−6. Data are presented as mean ± SD.
Althoff,
X-ray structures of GluCl in apo states reveal a gating mechanism of Cys-loop receptors.
2014, Pubmed
Althoff,
X-ray structures of GluCl in apo states reveal a gating mechanism of Cys-loop receptors.
2014,
Pubmed
Arcario,
A membrane-embedded pathway delivers general anesthetics to two interacting binding sites in the Gloeobacter violaceus ion channel.
2017,
Pubmed
Barrantes,
Lipid matters: nicotinic acetylcholine receptor-lipid interactions (Review).
2002,
Pubmed
Basak,
Cryo-EM structure of 5-HT3A receptor in its resting conformation.
2018,
Pubmed
,
Xenbase
Bocquet,
X-ray structure of a pentameric ligand-gated ion channel in an apparently open conformation.
2009,
Pubmed
Bussi,
Canonical sampling through velocity rescaling.
2007,
Pubmed
Chen,
Structural basis of neurosteroid anesthetic action on GABAA receptors.
2018,
Pubmed
,
Xenbase
Dawaliby,
Allosteric regulation of G protein-coupled receptor activity by phospholipids.
2016,
Pubmed
Du,
Glycine receptor mechanism elucidated by electron cryo-microscopy.
2015,
Pubmed
Dumas,
Is the protein/lipid hydrophobic matching principle relevant to membrane organization and functions?
1999,
Pubmed
Duncan,
Lipid-Dependent Regulation of Ion Channels and G Protein-Coupled Receptors: Insights from Structures and Simulations.
2020,
Pubmed
Gallivan,
Cation-pi interactions in structural biology.
1999,
Pubmed
Gharpure,
Agonist Selectivity and Ion Permeation in the α3β4 Ganglionic Nicotinic Receptor.
2019,
Pubmed
Hansen,
Structural basis of PIP2 activation of the classical inward rectifier K+ channel Kir2.2.
2011,
Pubmed
Hassaine,
X-ray structure of the mouse serotonin 5-HT3 receptor.
2014,
Pubmed
Hess,
P-LINCS: A Parallel Linear Constraint Solver for Molecular Simulation.
2008,
Pubmed
Hibbs,
Principles of activation and permeation in an anion-selective Cys-loop receptor.
2011,
Pubmed
Hilf,
X-ray structure of a prokaryotic pentameric ligand-gated ion channel.
2008,
Pubmed
Hilf,
Structure of a potentially open state of a proton-activated pentameric ligand-gated ion channel.
2009,
Pubmed
Huang,
Crystal structure of human glycine receptor-α3 bound to antagonist strychnine.
2015,
Pubmed
Huang,
Modulation of neuronal protein trafficking and function by palmitoylation.
2005,
Pubmed
Huang,
Direct activation of inward rectifier potassium channels by PIP2 and its stabilization by Gbetagamma.
1998,
Pubmed
,
Xenbase
Huang,
CHARMM36m: an improved force field for folded and intrinsically disordered proteins.
2017,
Pubmed
Hénault,
A lipid site shapes the agonist response of a pentameric ligand-gated ion channel.
2019,
Pubmed
,
Xenbase
Hénault,
The M4 Transmembrane α-Helix Contributes Differently to Both the Maturation and Function of Two Prokaryotic Pentameric Ligand-gated Ion Channels.
2015,
Pubmed
Jo,
CHARMM-GUI: a web-based graphical user interface for CHARMM.
2008,
Pubmed
Keller,
The gamma2 subunit of GABA(A) receptors is a substrate for palmitoylation by GODZ.
2004,
Pubmed
Khan,
Capturing Choline-Aromatics Cation-π Interactions in the MARTINI Force Field.
2020,
Pubmed
Khan,
Cation-π Interactions between Methylated Ammonium Groups and Tryptophan in the CHARMM36 Additive Force Field.
2019,
Pubmed
Killian,
How proteins adapt to a membrane-water interface.
2000,
Pubmed
Kim,
Shared structural mechanisms of general anaesthetics and benzodiazepines.
2020,
Pubmed
Knoflach,
Methods for the Discovery of Novel Compounds Modulating a Gamma-Aminobutyric Acid Receptor Type A Neurotransmission.
2018,
Pubmed
,
Xenbase
Lacin,
Dynamic role of the tether helix in PIP2-dependent gating of a G protein-gated potassium channel.
2017,
Pubmed
Laganowsky,
Membrane proteins bind lipids selectively to modulate their structure and function.
2014,
Pubmed
Laverty,
Cryo-EM structure of the human α1β3γ2 GABAA receptor in a lipid bilayer.
2019,
Pubmed
Laverty,
Crystal structures of a GABAA-receptor chimera reveal new endogenous neurosteroid-binding sites.
2017,
Pubmed
Long,
Atomic structure of a voltage-dependent K+ channel in a lipid membrane-like environment.
2007,
Pubmed
Martens,
Lipids modulate the conformational dynamics of a secondary multidrug transporter.
2016,
Pubmed
Masiulis,
GABAA receptor signalling mechanisms revealed by structural pharmacology.
2019,
Pubmed
McGibbon,
MDTraj: A Modern Open Library for the Analysis of Molecular Dynamics Trajectories.
2015,
Pubmed
Michaud-Agrawal,
MDAnalysis: a toolkit for the analysis of molecular dynamics simulations.
2011,
Pubmed
Miller,
Crystal structure of a human GABAA receptor.
2014,
Pubmed
Miller,
Structural basis for GABAA receptor potentiation by neurosteroids.
2017,
Pubmed
Morales-Perez,
X-ray structure of the human α4β2 nicotinic receptor.
2016,
Pubmed
Mouritsen,
Mattress model of lipid-protein interactions in membranes.
1984,
Pubmed
Mouritsen,
Models of lipid-protein interactions in membranes.
1993,
Pubmed
Muller,
Characterization of Lipid-Protein Interactions and Lipid-Mediated Modulation of Membrane Protein Function through Molecular Simulation.
2019,
Pubmed
Norimatsu,
Protein-phospholipid interplay revealed with crystals of a calcium pump.
2017,
Pubmed
Nowak,
In vivo incorporation of unnatural amino acids into ion channels in Xenopus oocyte expression system.
1998,
Pubmed
,
Xenbase
Nury,
X-ray structures of general anaesthetics bound to a pentameric ligand-gated ion channel.
2011,
Pubmed
Phulera,
Cryo-EM structure of the benzodiazepine-sensitive α1β1γ2S tri-heteromeric GABAA receptor in complex with GABA.
2018,
Pubmed
Polovinkin,
Conformational transitions of the serotonin 5-HT3 receptor.
2018,
Pubmed
Price,
FlexStation examination of 5-HT3 receptor function using Ca2+ - and membrane potential-sensitive dyes: advantages and potential problems.
2005,
Pubmed
Qi,
CHARMM-GUI Martini Maker for Coarse-Grained Simulations with the Martini Force Field.
2015,
Pubmed
Rahman,
Structure of the Native Muscle-type Nicotinic Receptor and Inhibition by Snake Venom Toxins.
2020,
Pubmed
Robinson,
Tools for Understanding Nanoscale Lipid Regulation of Ion Channels.
2019,
Pubmed
Sands,
How does a voltage sensor interact with a lipid bilayer? Simulations of a potassium channel domain.
2007,
Pubmed
Schmidt,
Phospholipids and the origin of cationic gating charges in voltage sensors.
2006,
Pubmed
Spurny,
Pentameric ligand-gated ion channel ELIC is activated by GABA and modulated by benzodiazepines.
2012,
Pubmed
,
Xenbase
Tong,
Direct binding of phosphatidylglycerol at specific sites modulates desensitization of a ligand-gated ion channel.
2019,
Pubmed
Walsh,
Structural principles of distinct assemblies of the human α4β2 nicotinic receptor.
2018,
Pubmed
Wassenaar,
Going Backward: A Flexible Geometric Approach to Reverse Transformation from Coarse Grained to Atomistic Models.
2014,
Pubmed
Wu,
Structure of a class C GPCR metabotropic glutamate receptor 1 bound to an allosteric modulator.
2014,
Pubmed
Yesylevskyy,
Polarizable water model for the coarse-grained MARTINI force field.
2010,
Pubmed
Zheng,
Lipid-dependent gating of a voltage-gated potassium channel.
2011,
Pubmed
Zhu,
Structure of a human synaptic GABAA receptor.
2018,
Pubmed
daCosta,
A distinct mechanism for activating uncoupled nicotinic acetylcholine receptors.
2013,
Pubmed
de Jong,
Improved Parameters for the Martini Coarse-Grained Protein Force Field.
2013,
Pubmed