Editors' ChoiceKinases

Kinase Sequence Belies Function

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Science's STKE  13 Jun 2000:
Vol. 2000, Issue 36, pp. tw6
DOI: 10.1126/stke.2000.36.tw6

As the sequences of more genes become available, scientists rely on sequence alignments and measurements of sequence similarity to predict the encoded protein's function. Xu et al. remind us of the hazards of this approach when they identified a novel protein from rat brain, WNK1, that has substantial similarity to serine-threonine kinases yet lacks the lysine that is highly conserved in the catalytic subdomain II of other characterized serine-threonine kinases. Based on the lack of this highly conserved residue, one might predict WNK1 not to have catalytic activity; however, a WNK1-glutathione-S-transferase fusion protein displayed kinase activity for itself and for myelin basic protein in vitro demonstrating that WNK1 is indeed catalytically active. Modeling WNK1 on the crystal structure of protein kinase A suggests that a lysine in subdomain I is able to substitute for the missing conserved lysine. Mutation of this subdomain I lysine in WNK1 resulted in an inactive protein confirming its importance in contributing to kinase activity of WNK1. WNK1 did not phosphorylate any of the tested members of the mitogen-activated protein kinase family in vitro assays; however, autophosphorylation was stimulated by exposure of cells to high salt, suggesting that WNK1 may be involved in osmosensing pathways.

Xu, B.-e., English, J.M., Wilsbacher, J.L., Stippec, S., Goldsmith, E.J., and Cobb, M.H. (2000) WNK1, a novel mammalian serine/threonine protein kinase lacking the catalytic lysine in subdomain II. J. Biol. Chem. 275: 16795-16801. [Abstract] [Full Text]

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