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Gating and selectivity mechanisms for the lysosomal K(+) channel TMEM175

Transmembrane protein 175 (TMEM175) is a K(+)-selective ion channel expressed in lysosomal membranes, where it establishes a membrane potential essential for lysosomal function and its dysregulation is associated with the development of Parkinson’s Disease. TMEM175 is evolutionarily distinct from al...

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Autores principales: Oh, SeCheol, Paknejad, Navid, Hite, Richard K
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141809/
https://www.ncbi.nlm.nih.gov/pubmed/32228865
http://dx.doi.org/10.7554/eLife.53430
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author Oh, SeCheol
Paknejad, Navid
Hite, Richard K
author_facet Oh, SeCheol
Paknejad, Navid
Hite, Richard K
author_sort Oh, SeCheol
collection PubMed
description Transmembrane protein 175 (TMEM175) is a K(+)-selective ion channel expressed in lysosomal membranes, where it establishes a membrane potential essential for lysosomal function and its dysregulation is associated with the development of Parkinson’s Disease. TMEM175 is evolutionarily distinct from all known channels, predicting novel ion-selectivity and gating mechanisms. Here we present cryo-EM structures of human TMEM175 in open and closed conformations, enabled by resolutions up to 2.6 Å. Human TMEM175 adopts a homodimeric architecture with a central ion-conduction pore lined by the side chains of the pore-lining helices. Conserved isoleucine residues in the center of the pore serve as the gate in the closed conformation. In the widened channel in the open conformation, these same residues establish a constriction essential for K(+) selectivity. These studies reveal the mechanisms of permeation, selectivity and gating and lay the groundwork for understanding the role of TMEM175 in lysosomal function.
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spelling pubmed-71418092020-04-10 Gating and selectivity mechanisms for the lysosomal K(+) channel TMEM175 Oh, SeCheol Paknejad, Navid Hite, Richard K eLife Structural Biology and Molecular Biophysics Transmembrane protein 175 (TMEM175) is a K(+)-selective ion channel expressed in lysosomal membranes, where it establishes a membrane potential essential for lysosomal function and its dysregulation is associated with the development of Parkinson’s Disease. TMEM175 is evolutionarily distinct from all known channels, predicting novel ion-selectivity and gating mechanisms. Here we present cryo-EM structures of human TMEM175 in open and closed conformations, enabled by resolutions up to 2.6 Å. Human TMEM175 adopts a homodimeric architecture with a central ion-conduction pore lined by the side chains of the pore-lining helices. Conserved isoleucine residues in the center of the pore serve as the gate in the closed conformation. In the widened channel in the open conformation, these same residues establish a constriction essential for K(+) selectivity. These studies reveal the mechanisms of permeation, selectivity and gating and lay the groundwork for understanding the role of TMEM175 in lysosomal function. eLife Sciences Publications, Ltd 2020-03-31 /pmc/articles/PMC7141809/ /pubmed/32228865 http://dx.doi.org/10.7554/eLife.53430 Text en © 2020, Oh et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Structural Biology and Molecular Biophysics
Oh, SeCheol
Paknejad, Navid
Hite, Richard K
Gating and selectivity mechanisms for the lysosomal K(+) channel TMEM175
title Gating and selectivity mechanisms for the lysosomal K(+) channel TMEM175
title_full Gating and selectivity mechanisms for the lysosomal K(+) channel TMEM175
title_fullStr Gating and selectivity mechanisms for the lysosomal K(+) channel TMEM175
title_full_unstemmed Gating and selectivity mechanisms for the lysosomal K(+) channel TMEM175
title_short Gating and selectivity mechanisms for the lysosomal K(+) channel TMEM175
title_sort gating and selectivity mechanisms for the lysosomal k(+) channel tmem175
topic Structural Biology and Molecular Biophysics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141809/
https://www.ncbi.nlm.nih.gov/pubmed/32228865
http://dx.doi.org/10.7554/eLife.53430
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