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Molecular mechanisms of acetylcholine receptor-lipid interactions: from model membranes to human biology.

ABSTRACT: Lipids are potent modulators of the Torpedo nicotinic acetylcholine receptor. Lipids influence nicotinic receptor function by allosteric mechanisms, stabilizing varying proportions of pre-existing resting, open, desensitized, and uncoupled conformations. Recent structures reveal that lipids could alter function by modulating transmembrane ?-helix/?-helix packing, which in turn could alter the conformation of the allosteric interface that links the agonist-binding and transmembrane pore domains-this interface is essential in the coupling of agonist binding to channel gating. We discuss potential mechanisms by which lipids stabilize different conformational states in the context of the hypothesis that lipid-nicotinic receptor interactions modulate receptor function at biological synapses.

SUBMITTER: Baenziger JE

PROVIDER: S-EPMC5425705 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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Molecular mechanisms of acetylcholine receptor-lipid interactions: from model membranes to human biology.

Baenziger John E JE daCosta Corrie J B CJB

Biophysical reviews 20120510 1

Lipids are potent modulators of the Torpedo nicotinic acetylcholine receptor. Lipids influence nicotinic receptor function by allosteric mechanisms, stabilizing varying proportions of pre-existing resting, open, desensitized, and uncoupled conformations. Recent structures reveal that lipids could alter function by modulating transmembrane α-helix/α-helix packing, which in turn could alter the conformation of the allosteric interface that links the agonist-binding and transmembrane pore domains-t ...[more]

PMID: 28510176

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Project description:M2delta, one of the transmembrane segments of the nicotinic acetylcholine receptor, is a 23-amino-acid peptide, frequently used as a model for peptide-membrane interactions. In this and the companion article we describe studies of M2delta-membrane interactions, using two different computational approaches. In the present work, we used continuum-solvent model calculations to investigate key thermodynamic aspects of its interactions with lipid bilayers. M2delta was represented in atomic detail and the bilayer was represented as a hydrophobic slab embedded in a structureless aqueous phase. Our calculations show that the transmembrane orientation is the most favorable orientation of the peptide in the bilayer, in good agreement with both experimental and computational data. Moreover, our calculations produced the free energy of association of M2delta with the lipid bilayer, which, to our knowledge, has not been reported to date. The calculations included 10 structures of M2delta, determined by nuclear magnetic resonance in dodecylphosphocholine micelles. All the structures were found to be stable inside the lipid bilayer, although their water-to-membrane transfer free energies differed by as much as 12 kT. Although most of the structures were roughly linear, a single structure had a kink in its central region. Interestingly, this structure was found to be the most stable inside the lipid bilayer, in agreement with molecular dynamics simulations of the peptide and with the recently determined structure of the intact receptor. Our analysis showed that the kink reduced the polarity of the peptide in its central region by allowing the electrostatic masking of the Gln13 side chain in that area. Our calculations also showed a tendency for the membrane to deform in response to peptide insertion, as has been previously found for the membrane-active peptides alamethicin and gramicidin. The results are compared to Monte Carlo simulations of the peptide-membrane system, as presented in the accompanying article.

Project description:α-Conotoxins selectively bind to nicotinic acetylcholine receptors (nAChRs), which are therapeutic targets due to their important role in signaling transmission in excitable cells. A previous experimental study has demonstrated that carboxylation of the C-terminal of α-conotoxin LsIA reduces its potency to inhibit human α7 nAChR relative to naturally amidated LsIA. However, little is known about the contribution of conformational changes in the receptor and interactions, induced by C-terminal amidation/carboxylation of conotoxins, to selective binding to nAChRs, since most conotoxins and some disulfide-rich peptides from other conotoxin subfamilies possess a naturally amidated C-terminal. In this study, we employ homology modeling and molecular dynamics (MD) simulations to propose the determinants for differential interactions between amidated and carboxylated LsIAs with α7 nAChR. Our findings indicate an overall increased number of contacts favored by binding of amidated LsIA versus its carboxylated counterpart. Toxin-receptor pairwise interactions, which may play a role in enhancing the potency of the former, include ARG10-TRP77, LEU141 and CYS17-GLN79 via persistent hydrogen bonds and cation-π interactions, which are weakened in the carboxylated form due to a strong intramolecular salt-bridge formed by ARG10 and carboxylated C-terminus. The binding of amidated LsIA also induces enhanced movements in loop C and the juxtamembrane Cys-loop that are closely associated with receptor function. Additionally, the impacts of binding of LsIA on the overall structure and inter-subunit contacts were examined using inter-residue network analysis, suggesting a clockwise tilting of the α7 C and F loops upon binding to carboxylated LsIA, which is absent for amidated LsIA binding. The predicted molecular mechanism of LsIA binding to the α7 receptor may provide new insights into the important role of the C-terminal in the binding potency of conotoxins at neuronal nAChRs for pharmacological purposes.

Dataset Information

Molecular mechanisms of acetylcholine receptor-lipid interactions: from model membranes to human biology.

Publications

Molecular mechanisms of acetylcholine receptor-lipid interactions: from model membranes to human biology.

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