Structural correlates of affinity in fetal versus adult endplate nicotinic receptors

Tapan Kumar Nayak, Srirupa Chakraborty, Wenjun Zheng and Anthony Auerbach ()
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Tapan Kumar Nayak: State University of New York at Buffalo
Srirupa Chakraborty: State University of New York at Buffalo
Wenjun Zheng: State University of New York at Buffalo
Anthony Auerbach: State University of New York at Buffalo

Nature Communications, 2016, vol. 7, issue 1, 1-14

Abstract: Abstract Adult-type nicotinic acetylcholine receptors (AChRs) mediate signalling at mature neuromuscular junctions and fetal-type AChRs are necessary for proper synapse development. Each AChR has two neurotransmitter binding sites located at the interface of a principal and a complementary subunit. Although all agonist binding sites have the same core of five aromatic amino acids, the fetal site has ∼30-fold higher affinity for the neurotransmitter ACh. Here we use molecular dynamics simulations of adult versus fetal homology models to identify complementary-subunit residues near the core that influence affinity, and use single-channel electrophysiology to corroborate the results. Four residues in combination determine adult versus fetal affinity. Simulations suggest that at lower-affinity sites, one of these unsettles the core directly and the others (in loop E) increase backbone flexibility to unlock a key, complementary tryptophan from the core. Swapping only four amino acids is necessary and sufficient to exchange function between adult and fetal AChRs.

Date: 2016
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DOI: 10.1038/ncomms11352

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