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Molecular basis for the binding and selective dephosphorylation of Na(+)/H(+) exchanger 1 by calcineurin
Very little is known about how Ser/Thr protein phosphatases specifically recruit and dephosphorylate substrates. Here, we identify how the Na(+)/H(+)-exchanger 1 (NHE1), a key regulator of cellular pH homeostasis, is regulated by the Ser/Thr phosphatase calcineurin (CN). NHE1 activity is increased b...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6677818/ https://www.ncbi.nlm.nih.gov/pubmed/31375679 http://dx.doi.org/10.1038/s41467-019-11391-7 |
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author | Hendus-Altenburger, Ruth Wang, Xinru Sjøgaard-Frich, Lise M. Pedraz-Cuesta, Elena Sheftic, Sarah R. Bendsøe, Anne H. Page, Rebecca Kragelund, Birthe B. Pedersen, Stine F. Peti, Wolfgang |
author_facet | Hendus-Altenburger, Ruth Wang, Xinru Sjøgaard-Frich, Lise M. Pedraz-Cuesta, Elena Sheftic, Sarah R. Bendsøe, Anne H. Page, Rebecca Kragelund, Birthe B. Pedersen, Stine F. Peti, Wolfgang |
author_sort | Hendus-Altenburger, Ruth |
collection | PubMed |
description | Very little is known about how Ser/Thr protein phosphatases specifically recruit and dephosphorylate substrates. Here, we identify how the Na(+)/H(+)-exchanger 1 (NHE1), a key regulator of cellular pH homeostasis, is regulated by the Ser/Thr phosphatase calcineurin (CN). NHE1 activity is increased by phosphorylation of NHE1 residue T779, which is specifically dephosphorylated by CN. While it is known that Ser/Thr protein phosphatases prefer pThr over pSer, we show that this preference is not key to this exquisite CN selectivity. Rather a combination of molecular mechanisms, including recognition motifs, dynamic charge-charge interactions and a substrate interaction pocket lead to selective dephosphorylation of pT779. Our data identify T779 as a site regulating NHE1-mediated cellular acid extrusion and provides a molecular understanding of NHE1 substrate selection by CN, specifically, and how phosphatases recruit specific substrates, generally. |
format | Online Article Text |
id | pubmed-6677818 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-66778182019-08-05 Molecular basis for the binding and selective dephosphorylation of Na(+)/H(+) exchanger 1 by calcineurin Hendus-Altenburger, Ruth Wang, Xinru Sjøgaard-Frich, Lise M. Pedraz-Cuesta, Elena Sheftic, Sarah R. Bendsøe, Anne H. Page, Rebecca Kragelund, Birthe B. Pedersen, Stine F. Peti, Wolfgang Nat Commun Article Very little is known about how Ser/Thr protein phosphatases specifically recruit and dephosphorylate substrates. Here, we identify how the Na(+)/H(+)-exchanger 1 (NHE1), a key regulator of cellular pH homeostasis, is regulated by the Ser/Thr phosphatase calcineurin (CN). NHE1 activity is increased by phosphorylation of NHE1 residue T779, which is specifically dephosphorylated by CN. While it is known that Ser/Thr protein phosphatases prefer pThr over pSer, we show that this preference is not key to this exquisite CN selectivity. Rather a combination of molecular mechanisms, including recognition motifs, dynamic charge-charge interactions and a substrate interaction pocket lead to selective dephosphorylation of pT779. Our data identify T779 as a site regulating NHE1-mediated cellular acid extrusion and provides a molecular understanding of NHE1 substrate selection by CN, specifically, and how phosphatases recruit specific substrates, generally. Nature Publishing Group UK 2019-08-02 /pmc/articles/PMC6677818/ /pubmed/31375679 http://dx.doi.org/10.1038/s41467-019-11391-7 Text en © The Author(s) 2019 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/. |
spellingShingle | Article Hendus-Altenburger, Ruth Wang, Xinru Sjøgaard-Frich, Lise M. Pedraz-Cuesta, Elena Sheftic, Sarah R. Bendsøe, Anne H. Page, Rebecca Kragelund, Birthe B. Pedersen, Stine F. Peti, Wolfgang Molecular basis for the binding and selective dephosphorylation of Na(+)/H(+) exchanger 1 by calcineurin |
title | Molecular basis for the binding and selective dephosphorylation of Na(+)/H(+) exchanger 1 by calcineurin |
title_full | Molecular basis for the binding and selective dephosphorylation of Na(+)/H(+) exchanger 1 by calcineurin |
title_fullStr | Molecular basis for the binding and selective dephosphorylation of Na(+)/H(+) exchanger 1 by calcineurin |
title_full_unstemmed | Molecular basis for the binding and selective dephosphorylation of Na(+)/H(+) exchanger 1 by calcineurin |
title_short | Molecular basis for the binding and selective dephosphorylation of Na(+)/H(+) exchanger 1 by calcineurin |
title_sort | molecular basis for the binding and selective dephosphorylation of na(+)/h(+) exchanger 1 by calcineurin |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6677818/ https://www.ncbi.nlm.nih.gov/pubmed/31375679 http://dx.doi.org/10.1038/s41467-019-11391-7 |
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