Cargando…

The Cryo-EM structure of pannexin 1 reveals unique motifs for ion selection and inhibition

Pannexins are large-pore forming channels responsible for ATP release under a variety of physiological and pathological conditions. Although predicted to share similar membrane topology with other large-pore forming proteins such as connexins, innexins, and LRRC8, pannexins have minimal sequence sim...

Descripción completa

Detalles Bibliográficos
Autores principales: Michalski, Kevin, Syrjanen, Johanna L, Henze, Erik, Kumpf, Julia, Furukawa, Hiro, Kawate, Toshimitsu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7108861/
https://www.ncbi.nlm.nih.gov/pubmed/32048993
http://dx.doi.org/10.7554/eLife.54670
_version_ 1783512851646775296
author Michalski, Kevin
Syrjanen, Johanna L
Henze, Erik
Kumpf, Julia
Furukawa, Hiro
Kawate, Toshimitsu
author_facet Michalski, Kevin
Syrjanen, Johanna L
Henze, Erik
Kumpf, Julia
Furukawa, Hiro
Kawate, Toshimitsu
author_sort Michalski, Kevin
collection PubMed
description Pannexins are large-pore forming channels responsible for ATP release under a variety of physiological and pathological conditions. Although predicted to share similar membrane topology with other large-pore forming proteins such as connexins, innexins, and LRRC8, pannexins have minimal sequence similarity to these protein families. Here, we present the cryo-EM structure of a frog pannexin 1 (Panx1) channel at 3.0 Å. We find that Panx1 protomers harbor four transmembrane helices similar in arrangement to other large-pore forming proteins but assemble as a heptameric channel with a unique constriction formed by Trp74 in the first extracellular loop. Mutating Trp74 or the nearby Arg75 disrupt ion selectivity, whereas altering residues in the hydrophobic groove formed by the two extracellular loops abrogates channel inhibition by carbenoxolone. Our structural and functional study establishes the extracellular loops as important structural motifs for ion selectivity and channel inhibition in Panx1.
format Online
Article
Text
id pubmed-7108861
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher eLife Sciences Publications, Ltd
record_format MEDLINE/PubMed
spelling pubmed-71088612020-04-01 The Cryo-EM structure of pannexin 1 reveals unique motifs for ion selection and inhibition Michalski, Kevin Syrjanen, Johanna L Henze, Erik Kumpf, Julia Furukawa, Hiro Kawate, Toshimitsu eLife Neuroscience Pannexins are large-pore forming channels responsible for ATP release under a variety of physiological and pathological conditions. Although predicted to share similar membrane topology with other large-pore forming proteins such as connexins, innexins, and LRRC8, pannexins have minimal sequence similarity to these protein families. Here, we present the cryo-EM structure of a frog pannexin 1 (Panx1) channel at 3.0 Å. We find that Panx1 protomers harbor four transmembrane helices similar in arrangement to other large-pore forming proteins but assemble as a heptameric channel with a unique constriction formed by Trp74 in the first extracellular loop. Mutating Trp74 or the nearby Arg75 disrupt ion selectivity, whereas altering residues in the hydrophobic groove formed by the two extracellular loops abrogates channel inhibition by carbenoxolone. Our structural and functional study establishes the extracellular loops as important structural motifs for ion selectivity and channel inhibition in Panx1. eLife Sciences Publications, Ltd 2020-02-12 /pmc/articles/PMC7108861/ /pubmed/32048993 http://dx.doi.org/10.7554/eLife.54670 Text en © 2020, Michalski 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 Neuroscience
Michalski, Kevin
Syrjanen, Johanna L
Henze, Erik
Kumpf, Julia
Furukawa, Hiro
Kawate, Toshimitsu
The Cryo-EM structure of pannexin 1 reveals unique motifs for ion selection and inhibition
title The Cryo-EM structure of pannexin 1 reveals unique motifs for ion selection and inhibition
title_full The Cryo-EM structure of pannexin 1 reveals unique motifs for ion selection and inhibition
title_fullStr The Cryo-EM structure of pannexin 1 reveals unique motifs for ion selection and inhibition
title_full_unstemmed The Cryo-EM structure of pannexin 1 reveals unique motifs for ion selection and inhibition
title_short The Cryo-EM structure of pannexin 1 reveals unique motifs for ion selection and inhibition
title_sort cryo-em structure of pannexin 1 reveals unique motifs for ion selection and inhibition
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7108861/
https://www.ncbi.nlm.nih.gov/pubmed/32048993
http://dx.doi.org/10.7554/eLife.54670
work_keys_str_mv AT michalskikevin thecryoemstructureofpannexin1revealsuniquemotifsforionselectionandinhibition
AT syrjanenjohannal thecryoemstructureofpannexin1revealsuniquemotifsforionselectionandinhibition
AT henzeerik thecryoemstructureofpannexin1revealsuniquemotifsforionselectionandinhibition
AT kumpfjulia thecryoemstructureofpannexin1revealsuniquemotifsforionselectionandinhibition
AT furukawahiro thecryoemstructureofpannexin1revealsuniquemotifsforionselectionandinhibition
AT kawatetoshimitsu thecryoemstructureofpannexin1revealsuniquemotifsforionselectionandinhibition
AT michalskikevin cryoemstructureofpannexin1revealsuniquemotifsforionselectionandinhibition
AT syrjanenjohannal cryoemstructureofpannexin1revealsuniquemotifsforionselectionandinhibition
AT henzeerik cryoemstructureofpannexin1revealsuniquemotifsforionselectionandinhibition
AT kumpfjulia cryoemstructureofpannexin1revealsuniquemotifsforionselectionandinhibition
AT furukawahiro cryoemstructureofpannexin1revealsuniquemotifsforionselectionandinhibition
AT kawatetoshimitsu cryoemstructureofpannexin1revealsuniquemotifsforionselectionandinhibition