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Structure and mechanism of the human NHE1-CHP1 complex
Sodium/proton exchanger 1 (NHE1) is an electroneutral secondary active transporter present on the plasma membrane of most mammalian cells and plays critical roles in regulating intracellular pH and volume homeostasis. Calcineurin B-homologous protein 1 (CHP1) is an obligate binding partner that prom...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8190280/ https://www.ncbi.nlm.nih.gov/pubmed/34108458 http://dx.doi.org/10.1038/s41467-021-23496-z |
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author | Dong, Yanli Gao, Yiwei Ilie, Alina Kim, DuSik Boucher, Annie Li, Bin Zhang, Xuejun C. Orlowski, John Zhao, Yan |
author_facet | Dong, Yanli Gao, Yiwei Ilie, Alina Kim, DuSik Boucher, Annie Li, Bin Zhang, Xuejun C. Orlowski, John Zhao, Yan |
author_sort | Dong, Yanli |
collection | PubMed |
description | Sodium/proton exchanger 1 (NHE1) is an electroneutral secondary active transporter present on the plasma membrane of most mammalian cells and plays critical roles in regulating intracellular pH and volume homeostasis. Calcineurin B-homologous protein 1 (CHP1) is an obligate binding partner that promotes NHE1 biosynthetic maturation, cell surface expression and pH-sensitivity. Dysfunctions of either protein are associated with neurological disorders. Here, we elucidate structures of the human NHE1-CHP1 complex in both inward- and inhibitor (cariporide)-bound outward-facing conformations. We find that NHE1 assembles as a symmetrical homodimer, with each subunit undergoing an elevator-like conformational change during cation exchange. The cryo-EM map reveals the binding site for the NHE1 inhibitor cariporide, illustrating how inhibitors block transport activity. The CHP1 molecule differentially associates with these two conformational states of each NHE1 monomer, and this association difference probably underlies the regulation of NHE1 pH-sensitivity by CHP1. |
format | Online Article Text |
id | pubmed-8190280 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-81902802021-07-01 Structure and mechanism of the human NHE1-CHP1 complex Dong, Yanli Gao, Yiwei Ilie, Alina Kim, DuSik Boucher, Annie Li, Bin Zhang, Xuejun C. Orlowski, John Zhao, Yan Nat Commun Article Sodium/proton exchanger 1 (NHE1) is an electroneutral secondary active transporter present on the plasma membrane of most mammalian cells and plays critical roles in regulating intracellular pH and volume homeostasis. Calcineurin B-homologous protein 1 (CHP1) is an obligate binding partner that promotes NHE1 biosynthetic maturation, cell surface expression and pH-sensitivity. Dysfunctions of either protein are associated with neurological disorders. Here, we elucidate structures of the human NHE1-CHP1 complex in both inward- and inhibitor (cariporide)-bound outward-facing conformations. We find that NHE1 assembles as a symmetrical homodimer, with each subunit undergoing an elevator-like conformational change during cation exchange. The cryo-EM map reveals the binding site for the NHE1 inhibitor cariporide, illustrating how inhibitors block transport activity. The CHP1 molecule differentially associates with these two conformational states of each NHE1 monomer, and this association difference probably underlies the regulation of NHE1 pH-sensitivity by CHP1. Nature Publishing Group UK 2021-06-09 /pmc/articles/PMC8190280/ /pubmed/34108458 http://dx.doi.org/10.1038/s41467-021-23496-z Text en © The Author(s) 2021 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 Dong, Yanli Gao, Yiwei Ilie, Alina Kim, DuSik Boucher, Annie Li, Bin Zhang, Xuejun C. Orlowski, John Zhao, Yan Structure and mechanism of the human NHE1-CHP1 complex |
title | Structure and mechanism of the human NHE1-CHP1 complex |
title_full | Structure and mechanism of the human NHE1-CHP1 complex |
title_fullStr | Structure and mechanism of the human NHE1-CHP1 complex |
title_full_unstemmed | Structure and mechanism of the human NHE1-CHP1 complex |
title_short | Structure and mechanism of the human NHE1-CHP1 complex |
title_sort | structure and mechanism of the human nhe1-chp1 complex |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8190280/ https://www.ncbi.nlm.nih.gov/pubmed/34108458 http://dx.doi.org/10.1038/s41467-021-23496-z |
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