Cell Signaling

Sensing Cellular Chloride

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Science  09 May 2014:
Vol. 344, Issue 6184, pp. 559
DOI: 10.1126/science.344.6184.559-a

Control of the concentration of chloride ions is critical for the proper function of neurons, control of blood pressure, regulation of cell volume, and other physiological functions. Piala et al. reveal the molecular basis of a cellular calcium sensor that enables such regulation. Chloride ions are moved across cell membranes by transporters, and the activities of several of such transporters are regulated by phosphorylation though a cascade of protein kinases, the first of which is known as WnK1 [with no lysine (K) 1]. This protein kinase, the authors show, is itself a sensor for chloride concentration. In crystal structures of WnK1 bound by chloride ions, the ion was bound to the catalytic site of the enzyme. This inhibited autophosporylation of the enzyme and thus would lead to activation of appropriate transporters when the concentration of chloride ions dipped below normal. This regulation mechanism is distinct from well-known examples in which calcium ions, for example, regulate kinase activity by binding to a separate regulatory subunit. Furthermore, it helps explain the unusual displacement of the catalytic lysine residue in WnK1, as the chloride binding site occupies the usual position of this essential lysine residue.

Sci. Signal. 7, ra41 (2014).

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