Molecular Investigation of Chicken Acid-Sensing Ion Channel 1 β11-12 Linker Isomerization and Channel Kinetics

Structures of the trimeric acid-sensing ion channel have been solved in the resting, toxin-bound open and desensitized states. Within the extracellular domain, there is little difference between the toxin-bound open state and the desensitized state. The main exception is that a loop connecting the 1...

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Autores principales:	Matthew L. Rook, Anna Ananchenko, Maria Musgaard, David M. MacLean
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	gating desensitization acid-sensing ion channels ASICs molecular dynamics Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571
Acceso en línea:	https://doaj.org/article/6d8fd25387bc46e9a27a83f62a2a78f1
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spelling	oai:doaj.org-article:6d8fd25387bc46e9a27a83f62a2a78f12021-12-02T12:03:05ZMolecular Investigation of Chicken Acid-Sensing Ion Channel 1 β11-12 Linker Isomerization and Channel Kinetics1662-510210.3389/fncel.2021.761813https://doaj.org/article/6d8fd25387bc46e9a27a83f62a2a78f12021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fncel.2021.761813/fullhttps://doaj.org/toc/1662-5102Structures of the trimeric acid-sensing ion channel have been solved in the resting, toxin-bound open and desensitized states. Within the extracellular domain, there is little difference between the toxin-bound open state and the desensitized state. The main exception is that a loop connecting the 11th and 12th β-strand, just two amino acid residues long, undergoes a significant and functionally critical re-orientation or flipping between the open and desensitized conformations. Here we investigate how specific interactions within the surrounding area influence linker stability in the “flipped” desensitized state using all-atom molecular dynamics simulations. An inherent challenge is bringing the relatively slow channel desensitization and recovery processes (in the milliseconds to seconds) within the time window of all-atom simulations (hundreds of nanoseconds). To accelerate channel behavior, we first identified the channel mutations at either the Leu414 or Asn415 position with the fastest recovery kinetics followed by molecular dynamics simulations of these mutants in a deprotonated state, accelerating recovery. By mutating one residue in the loop and examining the evolution of interactions in the neighbor, we identified a novel electrostatic interaction and validated prior important interactions. Subsequent functional analysis corroborates these findings, shedding light on the molecular factors controlling proton-mediated transitions between functional states of the channel. Together, these data suggest that the flipped loop in the desensitized state is stabilized by interactions from surrounding regions keeping both L414 and N415 in place. Interestingly, very few mutations in the loop allow for equivalent channel kinetics and desensitized state stability. The high degree of sequence conservation in this region therefore indicates that the stability of the ASIC desensitized state is under strong selective pressure and underlines the physiological importance of desensitization.Matthew L. RookAnna AnanchenkoMaria MusgaardDavid M. MacLeanFrontiers Media S.A.articlegatingdesensitizationacid-sensing ion channelsASICsmolecular dynamicsNeurosciences. Biological psychiatry. NeuropsychiatryRC321-571ENFrontiers in Cellular Neuroscience, Vol 15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	gating desensitization acid-sensing ion channels ASICs molecular dynamics Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571
spellingShingle	gating desensitization acid-sensing ion channels ASICs molecular dynamics Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571 Matthew L. Rook Anna Ananchenko Maria Musgaard David M. MacLean Molecular Investigation of Chicken Acid-Sensing Ion Channel 1 β11-12 Linker Isomerization and Channel Kinetics
description	Structures of the trimeric acid-sensing ion channel have been solved in the resting, toxin-bound open and desensitized states. Within the extracellular domain, there is little difference between the toxin-bound open state and the desensitized state. The main exception is that a loop connecting the 11th and 12th β-strand, just two amino acid residues long, undergoes a significant and functionally critical re-orientation or flipping between the open and desensitized conformations. Here we investigate how specific interactions within the surrounding area influence linker stability in the “flipped” desensitized state using all-atom molecular dynamics simulations. An inherent challenge is bringing the relatively slow channel desensitization and recovery processes (in the milliseconds to seconds) within the time window of all-atom simulations (hundreds of nanoseconds). To accelerate channel behavior, we first identified the channel mutations at either the Leu414 or Asn415 position with the fastest recovery kinetics followed by molecular dynamics simulations of these mutants in a deprotonated state, accelerating recovery. By mutating one residue in the loop and examining the evolution of interactions in the neighbor, we identified a novel electrostatic interaction and validated prior important interactions. Subsequent functional analysis corroborates these findings, shedding light on the molecular factors controlling proton-mediated transitions between functional states of the channel. Together, these data suggest that the flipped loop in the desensitized state is stabilized by interactions from surrounding regions keeping both L414 and N415 in place. Interestingly, very few mutations in the loop allow for equivalent channel kinetics and desensitized state stability. The high degree of sequence conservation in this region therefore indicates that the stability of the ASIC desensitized state is under strong selective pressure and underlines the physiological importance of desensitization.
format	article
author	Matthew L. Rook Anna Ananchenko Maria Musgaard David M. MacLean
author_facet	Matthew L. Rook Anna Ananchenko Maria Musgaard David M. MacLean
author_sort	Matthew L. Rook
title	Molecular Investigation of Chicken Acid-Sensing Ion Channel 1 β11-12 Linker Isomerization and Channel Kinetics
title_short	Molecular Investigation of Chicken Acid-Sensing Ion Channel 1 β11-12 Linker Isomerization and Channel Kinetics
title_full	Molecular Investigation of Chicken Acid-Sensing Ion Channel 1 β11-12 Linker Isomerization and Channel Kinetics
title_fullStr	Molecular Investigation of Chicken Acid-Sensing Ion Channel 1 β11-12 Linker Isomerization and Channel Kinetics
title_full_unstemmed	Molecular Investigation of Chicken Acid-Sensing Ion Channel 1 β11-12 Linker Isomerization and Channel Kinetics
title_sort	molecular investigation of chicken acid-sensing ion channel 1 β11-12 linker isomerization and channel kinetics
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/6d8fd25387bc46e9a27a83f62a2a78f1
work_keys_str_mv	AT matthewlrook molecularinvestigationofchickenacidsensingionchannel1b1112linkerisomerizationandchannelkinetics AT annaananchenko molecularinvestigationofchickenacidsensingionchannel1b1112linkerisomerizationandchannelkinetics AT mariamusgaard molecularinvestigationofchickenacidsensingionchannel1b1112linkerisomerizationandchannelkinetics AT davidmmaclean molecularinvestigationofchickenacidsensingionchannel1b1112linkerisomerizationandchannelkinetics
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Molecular Investigation of Chicken Acid-Sensing Ion Channel 1 β11-12 Linker Isomerization and Channel Kinetics

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