title: Mapping the conformational wave of acetylcholine receptor channel gating.
abstract: Allosteric transitions allow fast regulation of protein function in living systems. Even though the end points of such conformational changes are known for many proteins, the characteristics of the paths connecting these states remain largely unexplored. Rate-equilibrium linear free-energy relationships (LFERs) provide information about such pathways by relating changes in the free energy of the transition state to those of the ground states upon systematic perturbation of the system. Here we present an LFER analysis of the gating reaction pathway of the muscle acetylcholine receptor. We studied the closed <==> open conformational change at the single-molecule level following perturbation by series of single-site mutations, agonists and membrane voltages. This method provided a snapshot of several regions of the receptor at the transition state in terms of their approximate positions along the reaction coordinate, on a scale from 0 (closed-like) to 1 (open-like). The resulting map reveals a spatial gradient of positional values, which suggests that the conformational change proceeds in a wave-like manner, with the low-to-high affinity change at the transmitter-binding sites preceding the complete opening of the pore.
authors.affiliation: Department of Physiology and Biophysics, State University of New York at Buffalo, 14214, USA. grosman@buffalo.edu
authors.forename: C
authors.initials: C
authors.lastname: Grosman
authors.forename: M
authors.initials: M
authors.lastname: Zhou
authors.forename: A
authors.initials: A
authors.lastname: Auerbach
mesh_terms: D000494:Allosteric Regulation; D002460:Cell Line; D018679:Cholinergic Agonists / Q000494:pharmacology; D015640:Ion Channel Gating / Q000502:physiology*; D008564:Membrane Potentials; D009132:Muscles / Q000502:physiology; D017354:Point Mutation; D011487:Protein Conformation; D011950:Receptors, Cholinergic / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D013816:Thermodynamics
chemical_list: D018679:Cholinergic Agonists; D011950:Receptors, Cholinergic