Research ArticleStructural Biology

Chloride Sensing by WNK1 Involves Inhibition of Autophosphorylation

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Science Signaling  06 May 2014:
Vol. 7, Issue 324, pp. ra41
DOI: 10.1126/scisignal.2005050

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Inhibited by Chloride in the Active Site

Chloride ions are essential for regulation of blood pressure and electrolyte homeostasis. Kinases of the WNK family are involved in the phosphorylation-mediated regulation of chloride cotransporters and ion channels involved in salt regulation; mutations in WNK1 or WNK4 produce hypertension, hyperkalemia, and hyperchloremia. Piala et al. found that chloride ions stabilized the WNK1 kinase domain and inhibited its autophosphorylation activity and kinase activity toward substrates. Analysis of crystal structures of the kinase domain with either bromide or chloride revealed that the ion bound in the catalytic site, and mutation of the residues involved in binding the ion rendered the kinase less sensitive to inhibition of autophosphorylation activity by chloride salts. Thus, these results provide a molecular explanation for how these kinases function as sensors of intracellular chloride.

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