Structural correlates of human muscle nicotinic acetylcholine receptor subunit assembly mediated by δ(+) interface residues
Epstein, M.; Maxwell, S.; Piggot, T. J.; Beeson, D.; Bermudez, I.; Biggin, P. C.
Show abstract
Muscle nicotinic acetylcholine receptors are a class of heteropentameric ligand-gated cation channels with constituent subunits adopting a fixed stoichiometric arrangement. The specific amino acid residues that govern subunit ordering are however, only partially understood. By integrating all-atom molecular dynamics simulations, bioinformatics, two-electrode voltage clamp electrophysiology and 125I--bungarotoxin assays of chimeric nAChR subunits, we identify residues across the extracellular, transmembrane and extended M4 helix of the {delta} subunit that make structural signatures that contribute to intransigent assembly rules. Furthermore, functional differences observed in 2{delta}2{beta} receptors can be rationalized by changes in dynamical behavior that manifest themselves at the agonist binding site.
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