Functional anatomy of an allosteric protein

Nature Communications
Prasad PurohitAnthony Auerbach

Abstract

Synaptic receptors are allosteric proteins that switch on and off to regulate cell signalling. Here, we use single-channel electrophysiology to measure and map energy changes in the gating conformational change of a nicotinic acetylcholine receptor. Two separated regions in the α-subunits--the transmitter-binding sites and αM2-αM3 linkers in the membrane domain--have the highest ϕ-values (change conformation the earliest), followed by the extracellular domain, most of the membrane domain and the gate. Large gating-energy changes occur at the transmitter-binding sites, α-subunit interfaces, the αM1 helix and the gate. We hypothesize that rearrangements of the linkers trigger the global allosteric transition, and that the hydrophobic gate unlocks in three steps. The mostly local character of side-chain energy changes and the similarly high ϕ-values of separated domains, both with and without ligands, suggest that gating is not strictly a mechanical process initiated by the affinity change for the agonist.

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Citations

Nov 26, 2014·Proceedings of the National Academy of Sciences of the United States of America·Tapan K NayakAnthony Auerbach
May 2, 2015·The Journal of Physiology·Prasad PurohitAnthony Auerbach
Oct 27, 2015·Cell·Ben SorumLászló Csanády
Oct 28, 2015·The Journal of General Physiology·Ridhima VijAnthony Auerbach
Jul 25, 2015·Biochemical Pharmacology·Anthony Auerbach
Dec 3, 2014·Neuropharmacology·Anthony Auerbach
Oct 16, 2015·PloS One·Danilo Di MaioGiuseppe Brancato
Mar 16, 2017·ELife·Anaïs MennyPierre-Jean Corringer
Oct 29, 2017·Proceedings of the National Academy of Sciences of the United States of America·Tapan K Nayak, Anthony Auerbach
Apr 23, 2016·Nature Communications·Tapan Kumar NayakAnthony Auerbach
Jun 9, 2016·Nature Structural & Molecular Biology·Andrew J R Plested
Dec 15, 2015·Molecular Pharmacology·Anthony Auerbach
Nov 20, 2019·Journal of Computational Chemistry·Bogdan Lev, Toby W Allen
Jan 13, 2019·The Journal of General Physiology·Sushree TripathyAnthony Auerbach
Jan 13, 2019·The Journal of General Physiology·Tapan K NayakAnthony Auerbach
Dec 10, 2016·The Journal of General Physiology·Shaweta GuptaAnthony Auerbach
Jan 6, 2015·The Journal of Physiology·G Brent DaweDerek Bowie
Sep 11, 2020·The Journal of General Physiology·Anthony Auerbach
Jan 13, 2015·The Journal of Biological Chemistry·Suzanne ScottAngelo Keramidas
Jun 8, 2018·The Journal of Physiology·Derek Bowie
May 11, 2017·Proceedings of the National Academy of Sciences of the United States of America·Bogdan LevToby W Allen
Mar 7, 2021·Biophysical Journal·Dinesh C Indurthi, Anthony Auerbach
Apr 1, 2021·Proceedings of the National Academy of Sciences of the United States of America·Gisela D Cymes, Claudio Grosman
Jun 28, 2019·Chemical Reviews·Emelie FloodToby W Allen
Dec 5, 2014·Journal of the American Chemical Society·Ruth NussinovJin Liu

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