A release of local subunit conformational heterogeneity underlies gating in a muscle nicotinic acetylcholine receptor

Mackenzie J. Thompson, Farid Mansoub Bekarkhanechi, Anna Ananchenko, Hugues Nury and John E. Baenziger ()
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Mackenzie J. Thompson: University of Ottawa
Farid Mansoub Bekarkhanechi: University of Ottawa
Anna Ananchenko: University of Ottawa
Hugues Nury: Université Grenoble Alpes, CNRS, CEA, IBS
John E. Baenziger: University of Ottawa

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: Abstract Synaptic receptors respond to neurotransmitters by opening an ion channel across the post-synaptic membrane to elicit a cellular response. Here we use recent Torpedo acetylcholine receptor structures and functional measurements to delineate a key feature underlying allosteric communication between the agonist-binding extracellular and channel-gating transmembrane domains. Extensive mutagenesis at this inter-domain interface re-affirms a critical energetically coupled role for the principal α subunit β1-β2 and M2-M3 loops, with agonist binding re-positioning a key β1-β2 glutamate/valine to facilitate the outward motions of a conserved M2-M3 proline to open the channel gate. Notably, the analogous structures in non-α subunits adopt a locally active-like conformation in the apo state even though each L9’ hydrophobic gate residue in each pore-lining M2 α-helix is closed. Agonist binding releases local conformational heterogeneity transitioning all five subunits into a conformationally symmetric open state. A release of conformational heterogeneity provides a framework for understanding allosteric communication in pentameric ligand-gated ion channels.

Date: 2024
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DOI: 10.1038/s41467-024-46028-x

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