Journal article
Domains of WNK1 kinase in the regulation of ROMK1
American Journal of Physiology - Renal Physiology, Vol.295(2), pp.F438-F445
06/11/2008
DOI: 10.1152/ajprenal.90287.2008
PMCID: PMC2519181
PMID: 18550644
Abstract
WNK1 kinase belongs to a family of serine-threonine protein kinases with an atypical placement of the catalytic lysine. Increased expression of WNK1 causes hypertension and hyperkalemia in humans. WNK1 inhibits renal potassium channel ROMK1 by enhancing its endocytosis, likely contributing to hyperkalemia in affected patients. The domains of WNK1 involved in inhibition of ROMK1 have not been completely elucidated. Here, we reported that an NH
2
-terminal proline-rich domain (N-PRD; amino acids 1-119) is necessary and sufficient for WNK1 inhibition of ROMK1. A region (named “NL” for N-linker; amino acids 120-220) located between N-PRD and the kinase domain of WNK1 (amino acids 220-491) antagonized the inhibition of ROMK1 caused by N-PRD. The WNK1 kinase domain reversed the antagonism of NL on N-PRD. Mutagenesis studies revealed that charge-charge interactions between two conserved catalytic residues (Lys-233 and Asp-368) within the kinase domain (not the kinase activity) are critical for kinase domain to reverse the antagonism of NL domain. The WNK1 autoinhibitory domain (AID; amino acids 491-555) also affected ROMK, presumably by modulating the kinase domain conformation. Mutations of two conserved phenylalanine abolished the ability of AID to modulate ROMK1. Finally, the first coiled-coil domain (CC1; amino acids 555-640) of WNK1 alleviated the effect of AID domain toward kinase domain. Thus, multiple intra- and/or intermolecular interactions of WNK1 domains are at play for regulation of ROMK1 by WNK1.
Details
- Title: Subtitle
- Domains of WNK1 kinase in the regulation of ROMK1
- Creators
- Hao-Ran Wang - Division of Nephrology, Department of Medicine, UT Southwestern Medical Center, Dallas, TexasZhen Liu - The University of Texas Southwestern Medical CenterChou-Long Huang - Southwestern Medical Center
- Resource Type
- Journal article
- Publication Details
- American Journal of Physiology - Renal Physiology, Vol.295(2), pp.F438-F445
- Publisher
- American Physiological Society
- DOI
- 10.1152/ajprenal.90287.2008
- PMID
- 18550644
- PMCID
- PMC2519181
- ISSN
- 0363-6127
- eISSN
- 1522-1466
- Language
- English
- Date published
- 06/11/2008
- Academic Unit
- Nephrology; Internal Medicine
- Record Identifier
- 9984359912902771
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