Osmosensing by WNK Kinases

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

Research output: Contribution to journalArticlepeer-review

11 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1614-1623
Number of pages10
JournalMolecular biology of the cell
Issue number18
StatePublished - Aug 19 2021

ASJC Scopus subject areas

  • Medicine(all)


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