Molecular basis for the binding and selective dephosphorylation of Na+/H+ exchanger 1 by calcineurin
Sjøgaard-Frich, Lise M
Sheftic, Sarah R
Bendsøe, Anne H
Kragelund, Birthe B
Pedersen, Stine F
AffiliationUniv Arizona, Dept Chem & Biochem
MetadataShow full item record
CitationHendus-Altenburger, R., Wang, X., Sjøgaard-Frich, L. M., Pedraz-Cuesta, E., Sheftic, S. R., Bendsøe, A. H., ... & Peti, W. (2019). Molecular basis for the binding and selective dephosphorylation of Na+/H+ exchanger 1 by calcineurin. Nature communications, 10(1), 1-13.
JournalNATURE PUBLISHING GROUP
RightsCopyright © 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.
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AbstractVery 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.
NoteOpen access journal
VersionFinal published version
SponsorsLundbeck Foundation; National Institute of Neurological Disorders and Stroke [R01NS091336]; National Institute of General Medicine [R01GM098482]; Danish Council for Independent Research Natural Sciences [4181-00344]; Novo Nordisk Foundation [NNF18OC0034070]; US Department of Energy, Office of Science and Office of Basic Energy Sciences [DE-AC02-76SF00515]; DOE Office of Biological and Environmental Research; National Institutes of Health, National Institute of General Medical Sciences [P41GM103393]
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