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

TY - JOUR

T1 - Molecular basis for the binding and selective dephosphorylation of Na+/H+ exchanger 1 by calcineurin

AU - Hendus-Altenburger, Ruth

AU - Wang, Xinru

AU - Sjøgaard-Frich, Lise M.

AU - Pedraz Cuesta, Elena

AU - Sheftic, Sarah R.

AU - Bendsøe, Anne H.

AU - Page, Rebecca

AU - Kragelund, Birthe B.

AU - Pedersen, Stine F

AU - Peti, Wolfgang

PY - 2019/12/1

Y1 - 2019/12/1

N2 - 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.

AB - 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.

U2 - 10.1038/s41467-019-11391-7

DO - 10.1038/s41467-019-11391-7

M3 - Journal article

C2 - 31375679

SN - 2041-1723

VL - 10

JO - Nature Communications

JF - Nature Communications

M1 - 3489

ER -