An allosteric link connecting the lipid-protein interface to the gating of the nicotinic acetylcholine receptor

Scientific Reports
Jaimee A Domville, John E Baenziger

Abstract

The mechanisms underlying lipid-sensing by membrane proteins is of considerable biological importance. A unifying mechanistic question is how a change in structure at the lipid-protein interface is translated through the transmembrane domain to influence structures critical to protein function. Gating of the nicotinic acetylcholine receptor (nAChR) is sensitive to its lipid environment. To understand how changes at the lipid-protein interface influence gating, we examined how a mutation at position 418 on the lipid-facing surface of the outer most M4 transmembrane α-helix alters the energetic couplings between M4 and the remainder of the transmembrane domain. Human muscle nAChR is sensitive to mutations at position 418, with the Cys-to-Trp mutation resulting in a 16-fold potentiation in function that leads to a congenital myasthenic syndrome. Energetic coupling between M4 and the Cys-loop, a key structure implicated in gating, do not change with C418W. Instead, Trp418 and an adjacent residue couple energetically with residues on the M1 transmembrane α-helix, leading to a reorientation of M1 that stabilizes the open state. We thus identify an allosteric link connecting the lipid-protein interface of the nAChR to altered channel ...Continue Reading

References

Aug 5, 1990·Journal of Molecular Biology·A Horovitz, A R Fersht
Mar 28, 2002·Biophysical Journal·Cecilia BouzatSteven M Sine
Nov 3, 2004·Biochimica Et Biophysica Acta·Anthony G Lee
Feb 11, 2005·Journal of Molecular Biology·Nigel Unwin
Oct 12, 2005·The Journal of Biological Chemistry·Xinan XiuDennis A Dougherty
Dec 2, 2005·Proceedings of the National Academy of Sciences of the United States of America·Thomas GrutterJean-Pierre Changeux
May 11, 2006·Annals of Neurology·Xin-Ming ShenAndrew G Engel
Jun 1, 2006·The Journal of General Physiology·Ulrike LaitkoCatherine E Morris
Nov 28, 2007·The Journal of General Physiology·Archana JhaAnthony Auerbach
Sep 16, 2008·Proceedings of the National Academy of Sciences of the United States of America·Gareth T YoungNeil S Millar
Mar 13, 2009·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Won Yong LeeSteven M Sine
Apr 10, 2009·The Journal of Biological Chemistry·Corrie J B daCosta, John E Baenziger
Oct 10, 2009·The Journal of Biological Chemistry·Corrie J B daCostaJohn E Baenziger
Dec 22, 2009·Nature Structural & Molecular Biology·Svenja HaegerGünther Schmalzing
Jan 9, 2010·Biochimica Et Biophysica Acta·Jorge Mauricio Reyes-RuizRicardo Miledi
Aug 18, 2010·Neuropharmacology·John E Baenziger, Pierre-Jean Corringer
Oct 1, 2011·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Corrie J B daCostaSteven M Sine
Nov 16, 2011·The Journal of Biological Chemistry·Hai-Long WangSteven M Sine
Aug 18, 2012·Journal of the American Chemical Society·Kristina N-M DaefflerDennis A Dougherty
Mar 7, 2013·The Journal of Biological Chemistry·Jonathan M LabriolaJohn E Baenziger
Sep 10, 2013·Nature Chemical Biology·Corrie J B daCostaJohn E Baenziger
Oct 4, 2014·Journal of Molecular Biology·Florian CymerStephen H White
Oct 16, 2014·Neuropharmacology·Stuart A FormanKeith W Miller
Dec 19, 2014·The Journal of Biological Chemistry·Casey L CarswellJohn E Baenziger
Mar 21, 2015·Biochimica Et Biophysica Acta·John E BaenzigerJiayin Sun
Apr 4, 2015·Biochimica Et Biophysica Acta·Francisco J Barrantes

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Citations

Sep 8, 2018·BMC Neuroscience·Bijun Tang, Sarah C R Lummis
Oct 9, 2019·Nature Chemical Biology·Camille M HénaultChris Ulens
Apr 21, 2020·Biochimica Et Biophysica Acta. Biomembranes·Mackenzie J Thompson, John E Baenziger
May 5, 2020·ACS Chemical Neuroscience·Ana R G M da Costa CoutoSarah C R Lummis
Dec 10, 2020·ACS Chemical Neuroscience·Susanne M Mesoy, Sarah C R Lummis
Mar 6, 2019·ACS Chemical Neuroscience·Susanne MesoySarah C R Lummis

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Methods Mentioned

BETA
in vitro transcription

Software Mentioned

ELIC
GraphPad Prism

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