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Structures and gating mechanisms of human bestrophin anion channels
Bestrophin-1 (Best1) and bestrophin-2 (Best2) are two members of the bestrophin family of calcium (Ca(2+))-activated chloride (Cl(−)) channels with critical involvement in ocular physiology and direct pathological relevance. Here, we report cryo-EM structures of wild-type human Best1 and Best2 in va...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9253114/ https://www.ncbi.nlm.nih.gov/pubmed/35789156 http://dx.doi.org/10.1038/s41467-022-31437-7 |
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author | Owji, Aaron P. Wang, Jiali Kittredge, Alec Clark, Zada Zhang, Yu Hendrickson, Wayne A. Yang, Tingting |
author_facet | Owji, Aaron P. Wang, Jiali Kittredge, Alec Clark, Zada Zhang, Yu Hendrickson, Wayne A. Yang, Tingting |
author_sort | Owji, Aaron P. |
collection | PubMed |
description | Bestrophin-1 (Best1) and bestrophin-2 (Best2) are two members of the bestrophin family of calcium (Ca(2+))-activated chloride (Cl(−)) channels with critical involvement in ocular physiology and direct pathological relevance. Here, we report cryo-EM structures of wild-type human Best1 and Best2 in various states at up to 1.8 Å resolution. Ca(2+)-bound Best1 structures illustrate partially open conformations at the two Ca(2+)-dependent gates of the channels, in contrast to the fully open conformations observed in Ca(2+)-bound Best2, which is in accord with the significantly smaller currents conducted by Best1 in electrophysiological recordings. Comparison of the closed and open states reveals a C-terminal auto-inhibitory segment (AS), which constricts the channel concentrically by wrapping around the channel periphery in an inter-protomer manner and must be released to allow channel opening. Our results demonstrate that removing the AS from Best1 and Best2 results in truncation mutants with similar activities, while swapping the AS between Best1 and Best2 results in chimeric mutants with swapped activities, underlying a key role of the AS in determining paralog specificity among bestrophins. |
format | Online Article Text |
id | pubmed-9253114 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-92531142022-07-06 Structures and gating mechanisms of human bestrophin anion channels Owji, Aaron P. Wang, Jiali Kittredge, Alec Clark, Zada Zhang, Yu Hendrickson, Wayne A. Yang, Tingting Nat Commun Article Bestrophin-1 (Best1) and bestrophin-2 (Best2) are two members of the bestrophin family of calcium (Ca(2+))-activated chloride (Cl(−)) channels with critical involvement in ocular physiology and direct pathological relevance. Here, we report cryo-EM structures of wild-type human Best1 and Best2 in various states at up to 1.8 Å resolution. Ca(2+)-bound Best1 structures illustrate partially open conformations at the two Ca(2+)-dependent gates of the channels, in contrast to the fully open conformations observed in Ca(2+)-bound Best2, which is in accord with the significantly smaller currents conducted by Best1 in electrophysiological recordings. Comparison of the closed and open states reveals a C-terminal auto-inhibitory segment (AS), which constricts the channel concentrically by wrapping around the channel periphery in an inter-protomer manner and must be released to allow channel opening. Our results demonstrate that removing the AS from Best1 and Best2 results in truncation mutants with similar activities, while swapping the AS between Best1 and Best2 results in chimeric mutants with swapped activities, underlying a key role of the AS in determining paralog specificity among bestrophins. Nature Publishing Group UK 2022-07-04 /pmc/articles/PMC9253114/ /pubmed/35789156 http://dx.doi.org/10.1038/s41467-022-31437-7 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Owji, Aaron P. Wang, Jiali Kittredge, Alec Clark, Zada Zhang, Yu Hendrickson, Wayne A. Yang, Tingting Structures and gating mechanisms of human bestrophin anion channels |
title | Structures and gating mechanisms of human bestrophin anion channels |
title_full | Structures and gating mechanisms of human bestrophin anion channels |
title_fullStr | Structures and gating mechanisms of human bestrophin anion channels |
title_full_unstemmed | Structures and gating mechanisms of human bestrophin anion channels |
title_short | Structures and gating mechanisms of human bestrophin anion channels |
title_sort | structures and gating mechanisms of human bestrophin anion channels |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9253114/ https://www.ncbi.nlm.nih.gov/pubmed/35789156 http://dx.doi.org/10.1038/s41467-022-31437-7 |
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