Journal
AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY
Volume 295, Issue 2, Pages F438-F445Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajprenal.90287.2008
Keywords
clathrin-mediated endocytosis; protein-protein interaction; proline-rich motifs
Categories
Funding
- NIDDK NIH HHS [R01 DK059530-05A1, R01 DK059530, DK-59530] Funding Source: Medline
Ask authors/readers for more resources
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 NH2-terminal prolinerich 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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available