A structural and dynamic model for the nicotinic acetylcholine receptor

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Abstract

Folding of the five polypeptide subunits (α2βγδ), of the nicotinic acetylcholine receptor (AChR) into a functional structural model is described. The principles used to arrange the sequences into a structure include: (1) hydrophobicity → membrane‐crossing segments; (2) amphipathic character → ion‐carrying segments (ion channel with single group rotations); (3) molecular shape (elongated, pentagonal cylinder) → folding dimensions of exobilayer portion; (4) choice of acetylcholine binding sites → specific folding of exobilayer segments; (5) location of reducible disulfides (near agonist binding site) → additional specification of exobilayer arrangement; (6) genetic homology → consistency of functional group choices; (7) noncompetitive antagonist labeling → arrangement of bilayer helices. The AChR model is divided into three parts: (a) exobilayer consisting of 11 antiparallel β‐strands from each subunit; (b) bilayer consisting of four hydrophobic and one amphiphilic α‐helix from each subunit; (c) cytoplasmic consisting of one (folded) loop from each subunit. The exobilayer strands can form a closed ‘flower’ (the ‘resting state’) which is opened (‘activated’) by agonists bound perpendicular to the strands. Rearrangement of the agonists to a strand‐parallel position and partial closing of the ‘flower’ leads to a desensitized receptor. The actions of acetylcholine and succinoyl and suberoyl bis‐cholines are clarified by the model. The opening and closing of the exobilayer ‘flower’ controls access to the ion channel which is composed of the five amphiphilic bilayer helices. A molecular mechanism for ion flow in the channel is given. Openings interrupted by short duration closings (50 μs) depend upon channel group motions. The unusual photolabeling of intrabilayer serines in α, β and δ subunits but not in γ subunits near the binding site for non‐competitive antagonists is explained along with a mechanism for the action of these antagonists such as phencyclidine. The unusual α 192Cys–193Cys disulfide may have a special peptide arrangement, such as a cis‐peptide bond to a following proline (G.A. Petsko and E.M. Kosower, unpublished results). The position of phosphorylatable sites and proline‐rich segments are noted for the cytoplasmic loops. The dynamic behavior of the AChR channel and many different experimental results can be interpreted in terms of the model. An example is the lowering of ionic conductivity on substitution of bovine for Torpedoδ M2 segment. The model represents a useful construct for the design of experiments onAChR.

Original languageEnglish
Pages (from-to)431-449
Number of pages19
JournalEuropean Journal of Biochemistry
Volume168
Issue number2
DOIs
StatePublished - Oct 1987

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