Article Dans Une Revue Nature Communications Année : 2024

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

Résumé

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.

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Dates et versions

hal-04798845 , version 1 (22-11-2024)

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Citer

Mackenzie Thompson, Farid Mansoub Bekarkhanechi, Anna Ananchenko, Hugues Nury, John Baenziger. A release of local subunit conformational heterogeneity underlies gating in a muscle nicotinic acetylcholine receptor. Nature Communications, 2024, 15 (1), pp.1803. ⟨10.1038/s41467-024-46028-x⟩. ⟨hal-04798845⟩
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