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A flexible GAS belt responds to pore mutations changing the ion selectivity of proton-gated channels

Proton-gated ion channels conduct mainly Na(+) to induce postsynaptic membrane depolarization. Finding the determinants of ion selectivity requires knowledge of the pore structure in the open conformation, but such information is not yet available. Here, the open conformation of the hASIC1a channel...

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Autores principales: Chen, Zhuyuan, Lin, Sheng, Xie, Tianze, Lin, Jin-Ming, Canessa, Cecilia M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Rockefeller University Press 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8594623/
https://www.ncbi.nlm.nih.gov/pubmed/34766968
http://dx.doi.org/10.1085/jgp.202112978
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author Chen, Zhuyuan
Lin, Sheng
Xie, Tianze
Lin, Jin-Ming
Canessa, Cecilia M.
author_facet Chen, Zhuyuan
Lin, Sheng
Xie, Tianze
Lin, Jin-Ming
Canessa, Cecilia M.
author_sort Chen, Zhuyuan
collection PubMed
description Proton-gated ion channels conduct mainly Na(+) to induce postsynaptic membrane depolarization. Finding the determinants of ion selectivity requires knowledge of the pore structure in the open conformation, but such information is not yet available. Here, the open conformation of the hASIC1a channel was computationally modeled, and functional effects of pore mutations were analyzed in light of the predicted structures. The open pore structure shows two constrictions of similar diameter formed by the backbone of the GAS belt and, right beneath it, by the side chains of H28 from the reentrant loop. Models of nonselective mutant channels, but not those that maintain ion selectivity, predict enlargement of the GAS belt, suggesting that this motif is quite flexible and that the loss of stabilizing interactions in the central pore leads to changes in size/shape of the belt. Our results are consistent with the “close-fit” mechanism governing selectivity of hASIC1a, wherein the backbone of the GAS substitutes at least part of the hydration shell of a permeant ion to enable crossing the pore constriction.
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spelling pubmed-85946232021-11-17 A flexible GAS belt responds to pore mutations changing the ion selectivity of proton-gated channels Chen, Zhuyuan Lin, Sheng Xie, Tianze Lin, Jin-Ming Canessa, Cecilia M. J Gen Physiol Article Proton-gated ion channels conduct mainly Na(+) to induce postsynaptic membrane depolarization. Finding the determinants of ion selectivity requires knowledge of the pore structure in the open conformation, but such information is not yet available. Here, the open conformation of the hASIC1a channel was computationally modeled, and functional effects of pore mutations were analyzed in light of the predicted structures. The open pore structure shows two constrictions of similar diameter formed by the backbone of the GAS belt and, right beneath it, by the side chains of H28 from the reentrant loop. Models of nonselective mutant channels, but not those that maintain ion selectivity, predict enlargement of the GAS belt, suggesting that this motif is quite flexible and that the loss of stabilizing interactions in the central pore leads to changes in size/shape of the belt. Our results are consistent with the “close-fit” mechanism governing selectivity of hASIC1a, wherein the backbone of the GAS substitutes at least part of the hydration shell of a permeant ion to enable crossing the pore constriction. Rockefeller University Press 2021-11-12 /pmc/articles/PMC8594623/ /pubmed/34766968 http://dx.doi.org/10.1085/jgp.202112978 Text en © 2021 Chen et al. https://creativecommons.org/licenses/by/4.0/This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Chen, Zhuyuan
Lin, Sheng
Xie, Tianze
Lin, Jin-Ming
Canessa, Cecilia M.
A flexible GAS belt responds to pore mutations changing the ion selectivity of proton-gated channels
title A flexible GAS belt responds to pore mutations changing the ion selectivity of proton-gated channels
title_full A flexible GAS belt responds to pore mutations changing the ion selectivity of proton-gated channels
title_fullStr A flexible GAS belt responds to pore mutations changing the ion selectivity of proton-gated channels
title_full_unstemmed A flexible GAS belt responds to pore mutations changing the ion selectivity of proton-gated channels
title_short A flexible GAS belt responds to pore mutations changing the ion selectivity of proton-gated channels
title_sort flexible gas belt responds to pore mutations changing the ion selectivity of proton-gated channels
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8594623/
https://www.ncbi.nlm.nih.gov/pubmed/34766968
http://dx.doi.org/10.1085/jgp.202112978
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