page_title: WNK4
section_title: Structure
hierarchical_section_title: WNK4 / Structure
caption_attribution_description: English: The amino-acid (aa) positions of the domains are provided in parentheses. Some important PHAII mutations are localized in the acidic motif and calmodulin-binding domain, respectively.
context_page_description: 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 of 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 and the cortical collecting duct 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, also known as familial hyperkalemic hypertension or Gordon syndrome.
context_section_description: 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 the family. On the other hand, the N-terminal domain is unique in having a six-stranded instead of a five-stranded β sheet to form a complete β barrel.
  A chloride ion binding site has been identified in the region ³²⁰DLG³²³ of the kinase domain in WNK4. The binding of chloride Cl⁻ in this region inhibits the activation of WNK4. The autoinhibitory domain is a homolog of the RFXV-binding PASK/FRAY homology 2 (PF2) domain. Structural studies have revealed that the autoinhibitory domain consists of three β-strands and two α-helices. Notably, the RFXV‐binding groove is formed by the β3-αA interface of WNK proteins where RFXV peptide ligand interacts directly with residues Phe524, Asp531, and Glu539 of WNK1. The interaction between the RFXV motif and the autoinhibitory domain makes it possible for the C-terminal region of WNK4 to be in close proximity of the kinases domain and subsequently regulate its activity.
caption: Fig. 1. Domain structure of WNK4 and the positions of the initially identified PHAII-causing mutations. The amino-acid (aa) positions of the domains are provided in parentheses. Some important PHAII mutations are localized in the acidic motif and calmodulin-binding domain, respectively.
exif: {}