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

Journal Article · · Nature Communications
ORCiD logo [1]; ORCiD logo [2];  [3];  [4];  [5];  [6];  [5]; ORCiD logo [1]; ORCiD logo [4]; ORCiD logo [5]
  1. Univ. of Copenhagen (Denmark). Structural Biology and NMR Laboratory, Department of Biology
  2. Univ. of Arizona, Tucson, AZ (United States). Dept. of Chemistry and Biochemistry; Brown Univ., Providence, RI (United States). Dept. of Molecular Biology, Cell Biology and Biochemistry
  3. Univ. of Copenhagen (Denmark). Cell Biology and Physiology, Department of Biology
  4. Univ. of Copenhagen (Denmark). Cell Biology and Physiology, Department of Biology
  5. Univ. of Arizona, Tucson, AZ (United States). Dept. of Chemistry and Biochemistry
  6. Univ. of Copenhagen (Denmark). Structural Biology and NMR Laboratory, Department of Biology; Univ. of Copenhagen (Denmark). Cell Biology and Physiology, Department of Biology
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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.

Research Organization:
SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Biological and Environmental Research (BER)
Grant/Contract Number:
AC02-76SF00515; R01NS091336; R01GM098482
OSTI ID:
1624177
Journal Information:
Nature Communications, Vol. 10, Issue 1; ISSN 2041-1723
Publisher:
Nature Publishing GroupCopyright Statement
Country of Publication:
United States
Language:
English
Citation Metrics:
Cited by: 28 works
Citation information provided by
Web of Science

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Cited By (2)

The SLC9A-C Mammalian Na + /H + Exchanger Family: Molecules, Mechanisms, and Physiology journal October 2019
A dynamic charge-charge interaction modulates PP2A:B56 substrate recruitment journal March 2020

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