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

Author

Listed:
  • Ruth Hendus-Altenburger

    (University of Copenhagen)

  • Xinru Wang

    (University of Arizona
    Brown University)

  • 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
    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)

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.

Suggested Citation

  • 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 & Wolfgang Peti, 2019. "Molecular basis for the binding and selective dephosphorylation of Na+/H+ exchanger 1 by calcineurin," Nature Communications, Nature, vol. 10(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-11391-7
    DOI: 10.1038/s41467-019-11391-7
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    Cited by:

    1. Gautam Srivastava & Meng S. Choy & Nicolas Bolik-Coulon & Rebecca Page & Wolfgang Peti, 2023. "Inhibitor-3 inhibits Protein Phosphatase 1 via a metal binding dynamic protein–protein interaction," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    2. Idil Ulengin-Talkish & Matthew A. H. Parson & Meredith L. Jenkins & Jagoree Roy & Alexis Z. L. Shih & Nicole St-Denis & Gergo Gulyas & Tamas Balla & Anne-Claude Gingras & Péter Várnai & Elizabeth Coni, 2021. "Palmitoylation targets the calcineurin phosphatase to the phosphatidylinositol 4-kinase complex at the plasma membrane," Nature Communications, Nature, vol. 12(1), pages 1-19, December.

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