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Autoinhibition and Salt Sensing are Linked in the WNK1 Kinase

This research focuses on a 230kDa serine/threonine protein kinase known as WNK1 (With No lysine {K}), isoforms of which have been associated with a monogenic form of hypertension. Structural analysis of the autoinhibitory (AI) domain from WNK1 by NMR indicates that the RFXV binding site from the PASK/FRAY homology 2 (PF2) domain is conserved in the WNK1 AI domain. Titration data shows that incubation of RFXV peptides display extensive chemical shift perturbation as assessed by 1H, 15N‐HSQC. Size exclusion chromatography of the tethered construct of the AI and kinase domains show substantial conformational changes when dialyzed from high to low [NaCl]. Differential scanning fluorimetry conducted on the kinase domain shows that the domain undergoes a substantial increase in stabilization as the concentration of salt is increased. Further analysis of this phenomena points toward evidence of anion sensing. To corroborate this, the crystal structure of the activated WNK1 kinase domain was solved in low salt conditions. The kinase displays disorder of many key structural elements such as αC which is unsurprising given the DSF data. The coupling of the information gathered points to a mechanism of salt sensing and self‐contained signaling control in the WNK1 kinase.