WNK1
Encyclopedia
WNK lysine deficient protein kinase 1, also known as WNK1, is an enzyme which in humans is encoded by the WNK1 gene
. The human gene is located on short arm of chromosome 12 (12p13.3).
WNK1 is also known as Human Accelerated Region
5. It may, therefore, have played a key role in differentiating Humans from Ape
s.
followed by the kinase domain and a long C-terminal tail. The kinase domain has some similarity to the MEKK protein kinase
family.
.
The protein appears to be part of the ERK5 MAP kinase pathway upstream of MEKK2
/ MEKK3
and to function as a tetramer
. It selectively binds to and phosphorylates synaptotagmin 2 (SYT2
) within its calcium binding C2 domains. It activates the serum- and glucocorticoid-inducible protein kinase SGK1, leading to activation of the epithelial sodium channel
. It along with WNK4 stimulates clathrin-dependent endocytosis of renal outer medullar potassium 1 (ROMK1
). It (and WNK4
) interactes with intersectin (ITSN1
, ITSN2
).
s associated with Gordon hyperkalemia-hypertension syndrome (pseudohypoaldosteronism
Type II, featuring hypertension
) and congenital sensory neuropathy (HSAN
Type II, featuring loss of perception
to pain
, touch, and heat
due to a loss of peripheral sensory nerve
s). See also: HSN2 gene
.
, WNK3
, WNK4
).
Homologs of this protein have been found in Arabidopsis thaliana
, C. elegans
, Chlamydomonas reinhardtii
and Vitis vinifera
as well as in vertebrates including Danio rerio
and Taeniopygia guttata.
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
. The human gene is located on short arm of chromosome 12 (12p13.3).
WNK1 is also known as Human Accelerated Region
Human accelerated regions
Human accelerated regions , first described in August 2006, are a set of 49 segments of the human genome which are conserved throughout vertebrate evolution but are strikingly different in humans. They are named HAR1 through HAR49 according to their degree of difference between humans and chimpanzees...
5. It may, therefore, have played a key role in differentiating Humans from Ape
Ape
Apes are Old World anthropoid mammals, more specifically a clade of tailless catarrhine primates, belonging to the biological superfamily Hominoidea. The apes are native to Africa and South-east Asia, although in relatively recent times humans have spread all over the world...
s.
Structure
The WNK1 protein is composed of 2382 amino acids (molecular weight 230 kDa). The protein contains a small N-terminal domainProtein domain
A protein domain is a part of protein sequence and structure that can evolve, function, and exist independently of the rest of the protein chain. Each domain forms a compact three-dimensional structure and often can be independently stable and folded. Many proteins consist of several structural...
followed by the kinase domain and a long C-terminal tail. The kinase domain has some similarity to the MEKK protein kinase
MAP kinase kinase kinase
MAP kinase kinase kinase is a serine/threonine-specific protein kinase which acts upon MAP kinase kinase.In humans there are at least 19 genes:* MAP3K1 * MAP3K2* MAP3K3 * MAP3K4* MAP3K5...
family.
Function
The WNK1 gene encodes a cytoplasmic serine-threonine kinase expressed in the distal nephronNephron
The renal tubule is the portion of the nephron containing the tubular fluid filtered through the glomerulus. After passing through the renal tubule, the filtrate continues to the collecting duct system, which is not part of the nephron....
.
The protein appears to be part of the ERK5 MAP kinase pathway upstream of MEKK2
MAP3K2
Mitogen-activated protein kinase kinase kinase 2 is an enzyme that in humans is encoded by the MAP3K2 gene.-Interactions:MAP3K2 has been shown to interact with SH2D2A, MAP2K7, MAP2K5, XIAP and MAPK8.-Further reading:...
/ MEKK3
MAP3K3
Mitogen-activated protein kinase kinase kinase 3 is an enzyme that in humans is encoded by the MAP3K3 gene.-Interactions:MAP3K3 has been shown to interact with [SQSTM1/p62], MAP2K5, YWHAE, GAB1 and BRCA1.-Further reading:...
and to function as a tetramer
Tetramer
A tetramer is a protein with four subunits . There are homotetramers such as glutathione S-transferase or single-strand binding protein, dimers of hetero-dimers such as hemoglobin , and heterotetramers, where each subunit is different.-Subunit interactions in tetramers:The interactions between...
. It selectively binds to and phosphorylates synaptotagmin 2 (SYT2
SYT2
Synaptotagmin-2 is a protein that in humans is encoded by the SYT2 gene.-Further reading:...
) within its calcium binding C2 domains. It activates the serum- and glucocorticoid-inducible protein kinase SGK1, leading to activation of the epithelial sodium channel
Epithelial sodium channel
The epithelial sodium channel is a membrane-bound ion-channel that is permeable for Li+-ions, protons and especially Na+-ions. It is a constitutively active ion-channel...
. It along with WNK4 stimulates clathrin-dependent endocytosis of renal outer medullar potassium 1 (ROMK1
ROMK
ROMK is an acronym for the Renal Outer Medullary Potassium channel. This is an ATP-dependent potassium channel that transports potassium out of cells. It plays an important role in potassium recycling in the thick ascending limb and potassium secretion in the cortical collecting duct of the...
). It (and WNK4
WNK4
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.- Function :The WNK4 gene encodes a serine-threonine kinase expressed in distal nephron...
) interactes with intersectin (ITSN1
ITSN1
Intersectin-1 is a protein that, in humans, is encoded by the ITSN1 gene.-Interactions:ITSN1 has been shown to interact with SNAP-25, SOS1, SCAMP1 and CDC42.-Further reading:...
, ITSN2
ITSN2
Intersectin-2 is a protein that in humans is encoded by the ITSN2 gene.-Interactions:ITSN2 has been shown to interact with Wiskott-Aldrich syndrome protein.-Further reading:...
).
Clinical significance
WNK1 has mutationMutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
s associated with Gordon hyperkalemia-hypertension syndrome (pseudohypoaldosteronism
Pseudohypoaldosteronism
Pseudohypoaldosteronism is a condition that mimics hypoaldosteronism. However, the condition is due to a failure of response to aldosterone, and levels of aldosterone are actually elevated, due to a lack of feedback....
Type II, featuring hypertension
Hypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...
) and congenital sensory neuropathy (HSAN
Hereditary sensory and autonomic neuropathy
Hereditary sensory and autonomic neuropathy or hereditary sensory neuropathy is a condition used to describe any of the types of this disease which inhibit sensation.They are less common than Charcot-Marie-Tooth disease....
Type II, featuring loss of perception
Perception
Perception is the process of attaining awareness or understanding of the environment by organizing and interpreting sensory information. All perception involves signals in the nervous system, which in turn result from physical stimulation of the sense organs...
to pain
Pain
Pain is an unpleasant sensation often caused by intense or damaging stimuli such as stubbing a toe, burning a finger, putting iodine on a cut, and bumping the "funny bone."...
, touch, and heat
Heat
In physics and thermodynamics, heat is energy transferred from one body, region, or thermodynamic system to another due to thermal contact or thermal radiation when the systems are at different temperatures. It is often described as one of the fundamental processes of energy transfer between...
due to a loss of peripheral sensory nerve
Sensory nerve
Sensory nerves are nerves that receive sensory stimuli, such as how something feels and if it is painful, smooth, rough, etc.They are made up of nerve fibers, called sensory fibers .Sensory neurons are neurons that are activated by sensory input Sensory nerves are nerves that receive sensory...
s). See also: HSN2 gene
HSN2
Hereditary sensory neuropathy, type II also known as HSN2 is a protein which in humans in encoded by the HSN2. It is a single-exon ORF, and a nervous system-specific exon of the WNK1 gene...
.
Comparative genomics
The gene belongs to a group of four related protein kinases (WNK1, WNK2WNK2
Serine/threonine-protein kinase WNK2 is an enzyme that in humans is encoded by the WNK2 gene.-Further reading:...
, WNK3
WNK3
Serine/threonine-protein kinase WNK3, also known as protein kinase lysine-deficient 3, is a protein that in humans is encoded by the WNK3 gene.- Function :...
, WNK4
WNK4
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.- Function :The WNK4 gene encodes a serine-threonine kinase expressed in distal nephron...
).
Homologs of this protein have been found in Arabidopsis thaliana
Arabidopsis thaliana
Arabidopsis thaliana is a small flowering plant native to Europe, Asia, and northwestern Africa. A spring annual with a relatively short life cycle, arabidopsis is popular as a model organism in plant biology and genetics...
, C. elegans
Caenorhabditis elegans
Caenorhabditis elegans is a free-living, transparent nematode , about 1 mm in length, which lives in temperate soil environments. Research into the molecular and developmental biology of C. elegans was begun in 1974 by Sydney Brenner and it has since been used extensively as a model...
, Chlamydomonas reinhardtii
Chlamydomonas reinhardtii
Chlamydomonas reinhardtii is a single celled green alga about 10 micrometres in diameter that swims with two flagella. They have a cell wall made of hydroxyproline-rich glycoproteins, a large cup-shaped chloroplast, a large pyrenoid, and an "eyespot" that senses light.Although widely distributed...
and Vitis vinifera
Vitis vinifera
Vitis vinifera is a species of Vitis, native to the Mediterranean region, central Europe, and southwestern Asia, from Morocco and Portugal north to southern Germany and east to northern Iran....
as well as in vertebrates including Danio rerio
Danio rerio
The zebrafish, Danio rerio, is a tropical freshwater fish belonging to the minnow family of order Cypriniformes. It is a popular aquarium fish, frequently sold under the trade name zebra danio, and is an important vertebrate model organism in scientific research.-Taxonomy:The zebrafish are...
and Taeniopygia guttata.