6nuu
Structure of Calcineurin mutant in complex with NHE1 peptide
Structural highlights
FunctionPP2BA_HUMAN Calcium-dependent, calmodulin-stimulated protein phosphatase. This subunit may have a role in the calmodulin activation of calcineurin. Dephosphorylates DNM1L, HSPB1 and SSH1.[1] [2] Publication Abstract from PubMedVery 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. Molecular basis for the binding and selective dephosphorylation of Na(+)/H(+) exchanger 1 by calcineurin.,Hendus-Altenburger R, Wang X, Sjogaard-Frich LM, Pedraz-Cuesta E, Sheftic SR, Bendsoe AH, Page R, Kragelund BB, Pedersen SF, Peti W Nat Commun. 2019 Aug 2;10(1):3489. doi: 10.1038/s41467-019-11391-7. PMID:31375679[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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