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
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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]