Regulation of WNK1 by an autoinhibitory domain and autophosphorylation

Bing e. Xu, Xiaoshan Min, Steve Stippec, Byung Hoon Lee, Elizabeth J. Goldsmith, Melanie H. Cobb

Research output: Contribution to journalArticle

103 Citations (Scopus)

Abstract

WNK family protein kinases are large enzymes that contain the catalytic lysine in a unique position compared with all other protein kinases. These enzymes have been linked to a genetically defined form of hypertension. In this study we introduced mutations to test hypotheses about the position of the catalytic lysine, and we examined mechanisms involved in the regulation of WNK1 activity. Through the analysis of enzyme fragments and sequence alignments, we have identified an autoinhibitory domain of WNK1. This isolated domain, conserved in all four WNKs, suppressed the activity of the WNK1 kinase domain. Mutation of two key residues in this autoinhibitory domain attenuated its ability to inhibit WNK kinase activity. Consistent with these results, the same mutations in a WNK1 fragment that contain the autoinhibitory domain increased its kinase activity. We also found that WNK1 expressed in bacteria is autophosphorylated; autophosphorylation on serine 382 in the activation loop is required for its activity.

Original languageEnglish (US)
Pages (from-to)48456-48462
Number of pages7
JournalJournal of Biological Chemistry
Volume277
Issue number50
DOIs
StatePublished - Dec 13 2002

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Phosphotransferases
Protein Kinases
Mutation
Lysine
Enzymes
Sequence Alignment
Serine
Bacteria
Chemical activation
Hypertension

ASJC Scopus subject areas

  • Biochemistry

Cite this

Regulation of WNK1 by an autoinhibitory domain and autophosphorylation. / Xu, Bing e.; Min, Xiaoshan; Stippec, Steve; Lee, Byung Hoon; Goldsmith, Elizabeth J.; Cobb, Melanie H.

In: Journal of Biological Chemistry, Vol. 277, No. 50, 13.12.2002, p. 48456-48462.

Research output: Contribution to journalArticle

Xu, Bing e. ; Min, Xiaoshan ; Stippec, Steve ; Lee, Byung Hoon ; Goldsmith, Elizabeth J. ; Cobb, Melanie H. / Regulation of WNK1 by an autoinhibitory domain and autophosphorylation. In: Journal of Biological Chemistry. 2002 ; Vol. 277, No. 50. pp. 48456-48462.
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