Serine/threonine protein kinase WNK4 also known as WNK lysine deficient protein kinase 4 or WNK4, is an enzyme that in humans is encoded by the WNK4 gene. Missense mutations cause a genetic form of pseudohypoaldosteronism type 2, also called Gordon syndrome. WNK4 is a member of a serine/threonine kinase family that comprises four members. The family is so named because unlike other serine/threonine kinases, WNKs are characterized by the lack of the lysine in the subdomain II of the catalytic domain. Instead, a lysine in the β2 strand of subdomain I of the catalytic domain is responsible for the kinase activity. The WNK4 gene is located on chromosome 17q21-q22. It produces a 1,243-amino acid protein encoded by a 3,732-nucleotide open reading frame within a 4 kb cDNA transcript. WNK4 protein is highly expressed in the distal convoluted tubule (DCT) and the cortical collecting duct (CDD) of the kidney. WNK4 is also present in the brain, lungs, liver, heart, and colon of various mammalian species. Gene mutations in WNK4 has been found in patients with pseudohypoaldosteronism type II (PHAII), also known as familial hyperkalemic hypertension (FHHt) or Gordon syndrome. PHAII is an autosomal dominant hereditary disease characterized by hyperkalemia, hypertension, and metabolic acidosis. WNK4 plays a critical role in the regulation of various transporters and channels in the kidney. PHAII-causing mutations in WNK4 result in the dysregulation of renal sodium and potassium transporters and channels, leading to defects in sodium and potassium retention by the kidney, and in turn, elevated blood pressure and potassium level (hyperkalemia). Structure The tertiary structure of WNK4 has not been elucidated to date. Nevertheless, several individual domain structures of the protein are identified. These include a kinase domain near the amino terminus followed by an autoinhibitory domain, an acidic motif, two coiled-coil domains, and a calmodulin-binding domain in the C-terminal segment (Fig. 1). The structures for the kinase and autoinhibitory domains of WNK1 have been revealed. The high level of structural similarity between WNK4 and WNK1 allows us to deduce key structural details of WNK4 based on the insights gained from the corresponding regions within WNK1. The kinase domain of WNK4 has an 83% sequence identity with that of WNK1. The overall fold of the kinase domain of WNK1 resembles those of other protein kinases that have a typical dual-domain architecture. The C-terminal domain of WNK4 bears a high degree of similarity to other kinases within