A mechanism for acetylcholine receptor gating based on structure, coupling, phi, and flip

• DOI: 10.1085/jgp.201611673
• Publication Date: 2016-12-08T15:10:26Z
• Authors: Shaweta Gupta; Srirupa Chakraborty; Ridhima Vij; Anthony Auerbach
• Keywords: Models, Molecular; 0301 basic medicine; 0303 health sciences; Binding Sites; Molecular Conformation; Receptors, Nicotinic; Crystallography, X-Ray; 3. Good health; Mice; 03 medical and health sciences; Mutation; Animals; Ion Channel Gating; Research Articles

Nicotinic acetylcholine receptors are allosteric proteins that generate membrane currents by isomerizing ("gating") between resting and active conformations under the influence of neurotransmitters. Here, to explore mechanisms link transmitter-binding sites (TBSs) with distant gate, we use mutant cycle analyses measure coupling residue pairs, phi value sequence domain rearrangements, current simulations reproduce a microsecond shut component ("flip") apparent in single-channel recordings. Significant interactions amino acids separated >15 Å rare; an exception is αM2-M3 linkers TBSs ∼30 apart. Linker residues also make significant, local within subunits. Phi indicate without agonists, linker first region protein reach gating transition state. Together, pattern flip suggest complete, resting↔active involves passage through four brief intermediate states, events arising from sojourns all or subset. We derive energy landscapes for propose structure-based model which resting→active starts spontaneous rearrangements M2-M3 TBSs. These conformational changes stabilize twisted extracellular promote transmembrane helix tilting, gate dilation, formation "bubble" collapses initiate ion conduction. The twisting most energetically unfavorable step change rate-limiting reverse process bubble formation.