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UniProtKB/Swiss-Prot variant pages

UniProtKB/Swiss-Prot Q96J92: Variant p.Gln565Glu

Serine/threonine-protein kinase WNK4
Gene: WNK4
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Variant information Variant position: help 565 The position of the amino-acid change on the UniProtKB canonical protein sequence.
Type of variant: help LP/P [Disclaimer] The variants are classified into three categories: LP/P, LB/B and US.
  • LP/P: likely pathogenic or pathogenic.
  • LB/B: likely benign or benign.
  • US: uncertain significance
Residue change: help From Glutamine (Q) to Glutamate (E) at position 565 (Q565E, p.Gln565Glu). Indicates the amino acid change of the variant. The one-letter and three-letter codes for amino acids used in UniProtKB/Swiss-Prot are those adopted by the commission on Biochemical Nomenclature of the IUPAC-IUB.
Physico-chemical properties: help Change from medium size and polar (Q) to medium size and acidic (E) The physico-chemical property of the reference and variant residues and the change implicated.
BLOSUM score: help 2 The score within a Blosum matrix for the corresponding wild-type to variant amino acid change. The log-odds score measures the logarithm for the ratio of the likelihood of two amino acids appearing by chance. The Blosum62 substitution matrix is used. This substitution matrix contains scores for all possible exchanges of one amino acid with another:
  • Lowest score: -4 (low probability of substitution).
  • Highest score: 11 (high probability of substitution).
More information can be found on the following page
Variant description: help In PHA2B; impaired interaction with KLHL3. Any additional useful information about the variant.
Other resources: help Links to websites of interest for the variant.


Sequence information Variant position: help 565 The position of the amino-acid change on the UniProtKB canonical protein sequence.
Protein sequence length: help 1243 The length of the canonical sequence.
Location on the sequence: help PMAPGPPSVFPPEPEEPEAD Q HQPFLFRHASYSSTTSDCET The residue change on the sequence. Unless the variant is located at the beginning or at the end of the protein sequence, both residues upstream (20) and downstream (20) of the variant will be shown.
Residue conservation: help The multiple alignment of the region surrounding the variant against various orthologous sequences. 
Human                         PMAPGPPSVFPPEPEEPEADQHQPFLFRHASYSSTTSDCET

Mouse                         SLAPGPPSAFPPEPEEPEADQHQSFLFRHASYSSTTSDCET

Rat                           SMTPGPPSAFPPEPEEPEADQHQSFLFRHASYSSTTSDCET
Sequence annotation in neighborhood: help The regions or sites of interest surrounding the variant. In general the features listed are posttranslational modifications, binding sites, enzyme active sites, local secondary structure or other characteristics reported in the cited references. The "Sequence annotation in neighborhood" lines have a fixed format:
  • Type: the type of sequence feature.
  • Positions: endpoints of the sequence feature.
  • Description: contains additional information about the feature.
TypePositionsDescription
Chain 1 – 1243 Serine/threonine-protein kinase WNK4
Region 557 – 567 Interaction with KLHL3
Modified residue 575 – 575 Phosphoserine
Mutagenesis 575 – 575 S -> A. Abolished MAP3K15/ASK3-dependent phosphorylation.
Mutagenesis 575 – 575 S -> ED. Mimics phosphorylation without affecting WNK4 kinase activity.



Literature citations
Human hypertension caused by mutations in WNK kinases.
Wilson F.H.; Disse-Nicodeme S.; Choate K.A.; Ishikawa K.; Nelson-Williams C.; Desitter I.; Gunel M.; Milford D.V.; Lipkin G.W.; Achard J.-M.; Feely M.P.; Dussol B.; Berland Y.; Unwin R.J.; Mayan H.; Simon D.B.; Farfel Z.; Jeunemaitre X.; Lifton R.P.;
Science 293:1107-1112(2001)
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1); DISEASE; VARIANTS PHA2B LYS-562; ALA-564; GLU-565 AND CYS-1185; The CUL3-KLHL3 E3 ligase complex mutated in Gordon's hypertension syndrome interacts with and ubiquitylates WNK isoforms: disease-causing mutations in KLHL3 and WNK4 disrupt interaction.
Ohta A.; Schumacher F.R.; Mehellou Y.; Johnson C.; Knebel A.; Macartney T.J.; Wood N.T.; Alessi D.R.; Kurz T.;
Biochem. J. 451:111-122(2013)
Cited for: UBIQUITINATION; CHARACTERIZATION OF VARIANTS PHA2B LYS-562 AND GLU-565; Kelch-like 3 and Cullin 3 regulate electrolyte homeostasis via ubiquitination and degradation of WNK4.
Shibata S.; Zhang J.; Puthumana J.; Stone K.L.; Lifton R.P.;
Proc. Natl. Acad. Sci. U.S.A. 110:7838-7843(2013)
Cited for: UBIQUITINATION AT LYS-157; LYS-175; LYS-186; LYS-226; LYS-241; LYS-328; LYS-387; LYS-393; LYS-450; LYS-454; LYS-1010; LYS-1144; LYS-1157 AND LYS-1158; CHARACTERIZATION OF VARIANTS PHA2B LYS-562 AND GLU-565; Structural and biochemical characterization of the KLHL3-WNK kinase interaction important in blood pressure regulation.
Schumacher F.R.; Sorrell F.J.; Alessi D.R.; Bullock A.N.; Kurz T.;
Biochem. J. 460:237-246(2014)
Cited for: X-RAY CRYSTALLOGRAPHY (1.56 ANGSTROMS) OF 557-567 IN COMPLEX WITH KLHL2 AND KLHL3; UBIQUITINATION; CHARACTERIZATION OF VARIANTS PHA2B ALA-564 AND GLU-565;
Disclaimer: Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. They are not in any way intended to be used as a substitute for professional medical advice, diagnostic, treatment or care.