Osmosensing by WNK Kinases

Akella, Radha; Humphreys, John M.; Sekulski, Kamil; He, Haixia; Durbacz, Mateusz; Chakravarthy, Srinivas; Liwocha, Joanna; Mohammed, Zuhair J.; Brautigam, Chad A.; Goldsmith, Elizabeth J.

doi:10.1091/mbc.e20-01-0089

Title: Osmosensing by WNK Kinases

Journal Article · Thu Aug 19 00:00:00 EDT 2021 · Molecular Biology of the Cell

DOI:https://doi.org/10.1091/mbc.e20-01-0089· OSTI ID:1815032

Akella, Radha ^[1]; Humphreys, John M. ^[1]; Sekulski, Kamil ^[1]; He, Haixia ^[1]; Durbacz, Mateusz ^[1]; Chakravarthy, Srinivas ^[2]; Liwocha, Joanna ^[1]; Mohammed, Zuhair J. ^[3]; Brautigam, Chad A. ^[1]; Goldsmith, Elizabeth J. ^[1]

Univ. of Texas Southwestern Medical Center, Dallas, TX (United States)
APS/Illinois Inst. of Technology, Argonne, IL (United States)
Baylor College of Medicine, Houston, TX (United States)

With No Lysine (K) WNK kinases regulate electro-neutral cotransporters that are controlled by osmotic stress and chloride. We showed previously that autophosphorylation of WNK1 is inhibited by chloride, raising the possibility that WNKs are activated by osmotic stress. Here we demonstrate that unphosphorylated WNK isoforms 3 and 1 autophosphorylate in response to osmotic pressure in vitro, applied with the crowding agent polyethylene glycol (PEG)400 or osmolyte ethylene glycol (EG), and that this activation is opposed by chloride. Small angle x-ray scattering of WNK3 in the presence and absence of PEG400, static light scattering in EG, and crystallography of WNK1 were used to understand the mechanism. Osmosensing in WNK3 and WNK1 appears to occur through a conformational equilibrium between an inactive, unphosphorylated, chloride-binding dimer and an autophosphorylation-competent monomer. An improved structure of the inactive kinase domain of WNK1, and a comparison with the structure of a monophosphorylated form of WNK1, suggests that large cavities, greater hydration, and specific bound water may participate in the osmosensing mechanism. Our prior work showed that osmolytes have effects on the structure of phosphorylated WNK1, suggestive of multiple stages of osmotic regulation in WNKs.

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Research Organization:: Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER); National Institutes of Health (NIH)

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1815032

Journal Information:: Molecular Biology of the Cell, Vol. 32, Issue 18; ISSN 1059-1524

Publisher:: American Society for Cell BiologyCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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