Molecular basis for the binding and selective dephosphorylation of Na+/H+ exchanger 1 by calcineurin
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- Molecular basis for the binding and selective dephosphorylation of Na+ H+ exchanger 1 by calcineurin
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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.
Original language | English |
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Article number | 3489 |
Journal | Nature Communications |
Volume | 10 |
Number of pages | 13 |
ISSN | 2041-1723 |
DOIs | |
Publication status | Published - 2019 |
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