Molecular basis for the binding and selective dephosphorylation of Na+/H+ exchanger 1 by calcineurin

Ruth Hendus-Altenburger, Xinru Wang, Lise M. Sjøgaard-Frich, Elena Pedraz-Cuesta, Sarah R. Sheftic, Anne H. Bendsøe, Rebecca Page (), Birthe B. Kragelund (), Stine F. Pedersen () and Wolfgang Peti ()
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Ruth Hendus-Altenburger: University of Copenhagen
Xinru Wang: University of Arizona
Lise M. Sjøgaard-Frich: University of Copenhagen
Elena Pedraz-Cuesta: University of Copenhagen
Sarah R. Sheftic: University of Arizona
Anne H. Bendsøe: University of Copenhagen
Rebecca Page: University of Arizona
Birthe B. Kragelund: University of Copenhagen
Stine F. Pedersen: University of Copenhagen
Wolfgang Peti: University of Arizona

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-11391-7

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