Activation of the nicotinic acetylcholine receptor involves a switch in conformation of the alpha subunits.
The nicotinic acetylcholine (ACh) receptor belongs to a superfamily of synaptic ion channels that open in response to the binding of chemical transmitters. Their mechanism of activation is not known in detail, but a time-resolved electron microscopic study of the muscle-type ACh receptor had suggested that a local disturbance in the ligand-binding region and consequent rotations in the ligand-binding alpha subunits, connecting to the transmembrane portion, are involved. A more precise interpretation of this structural change is given here, based on comparison of the extracellular domain of the ACh receptor with an ACh-binding protein (AChBP) to which a putative agonist is bound. We find that, to a good approximation, there are two alternative extended conformations of the ACh receptor subunits, one characteristic of either alpha subunit before activation, and the other characteristic of all three non-alpha subunits and the protomer of AChBP. Substitution in the three-dimensional maps of alpha by non-alpha subunits mimics the changes seen on activation, suggesting that the structures of the alpha subunits are modified initially by their interactions with neighbouring subunits and switch to the non-alpha form when ACh binds. This structural change, which entails 15-16 degrees rotations of the inner pore-facing parts of the alpha subunits, most likely acts as the trigger that opens the gate in the membrane-spanning pore.
Unwin
N
N
MRC Laboratory of Molecular Biology, Neurobiology Division, Hills Road, Cambridge CB2 2QH, UK.
Miyazawa
A
A
Li
J
J
Fujiyoshi
Y
Y
D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism; D008854:Microscopy, Electron; D008958:Models, Molecular; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D021122:Protein Subunits; D011978:Receptors, Nicotinic / Q000737:chemistry* / Q000378:metabolism* / Q000648:ultrastructure; D014101:Torpedo
C428944:AChBP protein, Lymnaea; D002352:Carrier Proteins; D021122:Protein Subunits; D011978:Receptors, Nicotinic; D000109:Acetylcholine