Subunit Organization and Structure of an Acetylcholine Receptor

Abstract

We have learned the positions of the alpha-subunits around the AChR rosette and the location of the toxin on the synaptic crest. A charge/hydrophobic character map of the 40 A X 30 A receptor surface that binds alpha-bungarotoxin has been constructed. A beta-structure domain surrounds the agonist binding site on the alpha-subunits, as predicted by amphipathic Fourier sequence analysis. The ion channel may be constructed from five amphipathic helices, which insert into the bilayer as the alpha2 beta gamma delta subunits come together. They form a water-filled channel on one side and interface with hydrophobic helices in each subunit on the other.

Monoclonal antibodies specific to the beta and gamma subunits of the Torpedo acetylcholine receptor inhibit single-channel activity

“…The mechanism of mAb inhibition of channel function is unknown. Inhibition cannot be accounted for by steric hindrance as introduced by binding the large immunoglobulin molecule on the ACh receptor, since mAbs 35 and 6, which bind to the MIR and crosslink ACh receptors (Conti-Tronconi et al, 198 1;Fairclough et al, 1983;Lindstrom et al, 1983;Wan and Lindstrom, 1985) do not inhibit channel function. The inhibitory mAbs may act by crosslinking sites between adjacent subunits to prevent the sliding or rotation of subunits, thereby leading to an immobilized conformation of the ACh receptor.…”

Neurotoxin-Binding Site on The Acetylcholine Receptor

“…Al l of the side chain residues that have been identified as being important functionally are located on the concave surface of the molecule which comes into contact with the AChR (28). The residues which interact with the acetylicholine-binding site on the AChR lie at the end of neurotoxin loop 2, the.…”

“…'The cationlic guanidinium group of the invariant arginine-37 of the neurotoxin is considered to be the counterpart of the quaternary ammonium group of acetylcholine (20)(21)(22)(23). Most likely, an anionic site on the ACfiR lying beneatil argirine-37 of the toxins forms part of the acetylcholine-bonding site (28). Other toxin residues participate in binding to the AW.hR (28,29' and such multipoint interactions may be responsible for the high affinity of toxin binding (30).…”

“…Several models of the secondary structure of the a-subunit of the AC'R have be.n proposed (11,28,(31)(32)(33)(34)(35).…”

“…The snake venom neurotoxins are flat, hand-shaped molecules with three polypeptide loops projecting from a central core of four disulfide bridges near one end (20)(21)(22)(23)(24)(25)(26)(27)(28).…”