Journal
JOURNAL OF MOLECULAR BIOLOGY
Volume 425, Issue 8, Pages 1245-1252Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jmb.2013.01.031
Keywords
WNK1; protein kinase; autoinhibitory domain; NMR; PF2
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Funding
- Cancer Prevention and Research Institute of Texas (CPRIT) [100941]
- Robert A. Welch Foundation [I1128, I1424]
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WNK1 [with no lysine (K)-1] is a 250-kDa serine/threonine protein kinase involved in the maintenance of cellular salt levels and is directly linked to a hereditary form of hypertension. Here, we report the solution NMR structure of the autoinhibitory domain of WNK1 (WNK1-Al), a small regulatory subunit that lies immediately C-terminal of the kinase domain. We show that this domain is a homolog of the RFXV-binding PASK/FRAY homology 2 (PF2) domain found in OSR (oxidative stress responsive) and SPAK (serine/threonine proline-alanine-rich) kinases, which are substrates of WNK1. The WNK1-Al has a circularly permuted topology relative to the OSR1-PF2 domain. Nevertheless, like PF2 domains, WNK1-Al binds peptides that contain an RFXV motif with micromolar affinities as assessed by changes in H-1, N-15 heteronuclear single quantum coherence spectra. Mutations to the WNK1-Al and binding peptides confirm a similar binding mode. (C) 2013 Published by Elsevier Ltd.
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