Abstract
The gating of pentameric ligand gated ion channels (pLGICs) is sensitive to a variety of allosteric modulators that act on the transmembrane domain, including lipids. Here, we use two prokaryotic homologs, GLIC and ELIC, to examine the role of the lipid-exposed transmembrane a-helix, M4, in the allosteric regulation of pLGICs. Aromatic interactions at the interface between M4 and the adjacent a-helices, M1 and M3, drive M4 binding during folding (Haeger et al. (2010) Nat Struct Mol Biol 17:90-98). Alanine substitutions of the aromatics at this interface in GLIC weaken M4 binding and inhibit channel function, while aromatic substitutions of aliphatic residues at the same interface in ELIC promote M4 binding and potentiate channel function. The strength of M4 binding to M1/M3 governs the susceptibility of both pLGICs to the potentiating effects of a congenital myasthenic syndrome mutation, which occurs in muscle-type nicotinic receptors on the lipid-facing surface of M4 and alters lipid-protein interactions to enhance function, but has little effect on the inhibitory activity of the drug, propofol. We thus identify both M4-dependent and M4-independent pathways for transmembrane domain allosteric regulation. Our data suggest that the chemistry at the interface between M4 and M1/M3 influences the intrinsic M4 binding affinity for M1/M3 and may thus govern the susceptibility of a pLGIC to the potentiating effects of lipids.
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