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Theoretical Structure of WNK1

WNK1

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From Wikipedia, the free encyclopedia


WNK (lysine deficient protein kinase 1), also known as WNK1, is an enzyme that is encoded by the WNK1 gene.[1][2][3][4][5] WNK1 is serine-threonine kinase and part of the "with no lysine/K" kinase WNK family.[1][2][3][5] The predominant role of WNK1 is the regulation of cation-Cl- cotransporters (CCCs) such as the sodium chloride cotransporter (NCC), basolateral Na-K-Cl symporter (NKCC1), and potassium chloride cotransporter (KCC1) located within the kidney.[1][2][5] CCCs mediate ion homeostasis and modulate blood pressure by transporting ions in and out of the cell.[1] WNK1 mutations as a result have been implicated in blood pressure disorders/diseases; a prime example being familial hyperkalemic hypertension (FHHt).[1][2][3][4][5]

Contents

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Structure[edit]

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The WNK1 protein is composed of 2382 amino acids (molecular weight 230 kDa).[4] The protein contains a kinase domain located within its short N-terminaldomain and a long C-terminal tail.[4] The kinase domain has some similarity to the MEKK protein kinase family.[4] As a member of the WNK family, the kinase's catalytic lysine residue is uniquely located in beta strand 2 of the glycine loop.[4] In order to have kinase activity, WNK1 must autophosphorylate the serine 382 residue found in its activation loop.[4][1] Further, phosphorylation at another site (Ser378) increases WNK1 activity.[1]An autoinhibitory domain is located within the C-terminal domain along with a HQ domain that is needed for WNK1 interactions with other WNKs.[1][2][3][4] The interactions between WNKs play an important role in function; WNK1 mutants that lack an HQ domain also lack kinase activity.

Function[edit]

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The WNK1 gene encodes a cytoplasmic serine-threonine kinase expressed in the distal nephron.[1][2][4] Studies have shown that WNK1 can activate multiple CCCs.[1][2] WNK1 however, does not directly phosphorylate the CCCs themselves rather it phosphorylates other serine-threonine kinases: Sterile20 related proline-alanine-rich kinase (SPAK) and oxidative stress response kinase 1 (OXSR1).[2][1][3] Phosphorylation of SPAK's T loop located in its catalytic domain will activate SPAK, which will go on to phosphorylation the CCC's N-terminaldomain.[1][2] Hence, WNK1 activates CCCs indirectly as an upstream regulator of SPAK/OSR1.[1][2][3]

WNK1 monomers interact to form a WNK1 homodimer that phosphorylates SPAK/OSR1 kinases which then phosphorylate the sodium chloride cotransporter (NCC). Once phosphorylated, the NCC activates to transport Na+ and Cl- ions into the cell.
File:WNK1 SGK1 ENaC.png
WNK1 phosphorylates SGK1 that will drive increased expression of ENaC.

Sodium Reabsorption

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In the distal convoluted tubule (DCT), WNK1 is a potent activator of the NCC that results in an increase in sodium re absorption that drives an increase in blood pressure.[1][2][3] The WNK1 mutant found in FHHt harbors a large deletion within intron 1 that causes an increase in the expression of full length WNK1.[1][2][3][4] The boost in WNK1 leads to increases in NCC activation that promotes the high blood pressure/hypertension associated with FHHt.[1][2][3][4] WNK1 activates the serum-and glucocorticoid-inducible protein kinase SGK1, leading to increased expression of the epithelial sodium channel (ENaC), which also promotes sodium re absorption.[2]

Potassium Secretion

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WNK1 regulates potassium channels found in the cortical collecting duct (CCD) and connecting tubule (CNT).[2] Renal outer medullar potassium 1 (ROMK1) and large conductance calcium-activated potassium channel (BKCa) are the two primary channels for potassium secretion.[2] WNK1 indirectly stimulates clathrin-dependent endocytosis of ROMK1 by a potential interaction with intersectin (ITSN1); thus, kinase activity is not needed.[2] Another possible mechanism of ROMK1 regulation is via autosomal recessive hypercholeserolemia (ACH), which is a clathrin adaptor molecule.[2] ACH phosporylation by WNK1 promotes the translocation of ROMK1 to clathrin coated pits triggering endocytosis.[2] WNK1 may indirectly activate BKCa by inhibiting the actions of extracellular signal–regulated kinases (ERK1 and ERK2) that lead to lysomal degradation.[2]

Cell Volume Regulation

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The NKCC1/2 cotransporters are regulated by intracellular Cl- concentration.[5] Studies point to WNK1 as key effector that couples Cl- concentration to NKCC1/2 function.[1][5] In hypertonic (high extracellular Cl- ) conditions that trigger cell shrinkage, an unknown mechanism upregulates WNK1 expression to counteract the volume loss.[1] The increased WNK1 leads to activation of SPAK/OSR1 that activate NKCC1/2 via subsequent phosphorylation.[1][5] NKCC1/2 will promote the influx of Na+, K+, and Cl- ions into the cell thereby causing the flow of water into the cell.[1] In the reverse circumstances, where hypotonic (low extracellular Cl- ) conditions induce cell swelling, WNK1 is inhibited.[1] Another cotransporter, KCC is inactive when phosphorylated; without activated WNK1, KCC does not undergo phosphorylation and can activate.[1] The cotransporter will promote the efflux of K+ and Cl- ions and cause the flow of water out of the cell to combat swelling.[1]

WNK1 in the Brain

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In the mature brain, the GABA neurotransmitter represents the major inhibitory signal used in neuronal signaling.[1] GABA activates the GABAA receptor which is a Cl- ion channel.[1] Cl- ions will enter the neuron causing hyperpolarization and inhibition of signaling.[1] During brain development however, GABAA activation will allow Cl- ions to leave the neuron causing the neuron to depolarize.[1] Thus, GABA is an excitatory neurotransmitter during development.[1] WNK1 has been implicated in the developmental switch from excitatory to inhibitory GABA signaling via interaction with NKCC1 and KCCs.[1] WNK1 phosphorylates SPAK/OSR1 which then phosphorylates KCC2 inhibiting the flow of Cl- ions out of the cell during development.[1]

WNK4 can bind WNK1 leading to inhibition of WNK1 activity. Cl- ions can also bind WNK1 and inhibit its activity when the Cl- concentration is high within the cell.

Regulation of WNK1

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The concentrations of Cl- ions and K+ ion play a major role in regulating WNK1 activity.[1][5] In the DCT, the plasma concentration of K+ ion is thought to impact the concentration Cl- ions within the nephron.[1][5] High plasma K+ concentration down regulates WNK1 activity and prevents Cl- ion from entering the nephron via the NCC.[1][5] The opposite occurs when plasma K+ concentration is low; increased WNK1 activity boosts NCC activity promoting reabsorption of Cl- ions.[1][5] When there is an abundance of Cl- ions within the nephron, WNK1 activity is inhibited by the binding of a Cl- ion to WNK1's catalytic domain.[1][5]

Furthermore, WNK1 and WNK4 may interact to form heterodimers that inhibit WNK1 function.[3][2] WNK4 release from the heterodimer allows WNK1 monomer to bind another WNK1 monomer to promote activation.[2][3] WNK1 function can also be inhibited if WNK1 is degraded. There are two enzymes responsible for WNK1 ubiquitination, kelch like 3 (KLHL3) and cullin 3 (CUL3).[3][2][6]KLHL3 serves as an adaptor protein that promotes the interaction between WNK1 and Cullin3, which is in a complex containing an E3 ubquitin ligase that attaches the ubiquitin molecules to WNK1.[3] The ubiquitinated WNK1 will subsequently undergo proteasomal degradation.[3][2][6] 

Clinical significance[edit]

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WNK1 has mutations associated with Gordon hyperkalemia-hypertension syndrome (pseudohypoaldosteronism Type II, featuring hypertension also called familial hyperkalemic hypertension (FHHt) )[1][3][4] and congenital sensory neuropathy (HSAN Type II, featuring loss of perception to paintouch, and heat due to a loss of peripheral sensory nerves)[1][7]See also: HSN2 gene.

Comparative genomics[edit]

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The gene belongs to a group of four related protein kinases (WNK1, WNK2WNK3WNK4)[1][3][4].

Homologs of this protein have been found in Arabidopsis thalianaC. elegansChlamydomonas reinhardtii and Vitis viniferaas well as in vertebrates including Danio rerio and Taeniopygia guttata.[3]

References[edit]

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  1. Jump up to:a b c
  1. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad ae af ag ah ai aj ak al Shekarabi, Masoud; Zhang, Jinwei; Khanna, Arjun R.; Ellison, David H.; Delpire, Eric; Kahle, Kristopher T. (2017-02-07). "WNK Kinase Signaling in Ion Homeostasis and Human Disease". Cell Metabolism. 25 (2): 285–299. doi:10.1016/j.cmet.2017.01.007. ISSN 1932-7420. PMID 28178566.
  2. ^ a b c d e f g h i j k l m n o p q r s t u v w x Hadchouel, Juliette; Ellison, David H.; Gamba, Gerardo (2016). "Regulation of Renal Electrolyte Transport by WNK and SPAK-OSR1 Kinases". Annual Review of Physiology. 78: 367–389. doi:10.1146/annurev-physiol-021115-105431. ISSN 1545-1585. PMID 26863326.
  3. ^ a b c d e f g h i j k l m n o p q Bazúa-Valenti, Silvana; Gamba, Gerardo (2015-05-15). "Revisiting the NaCl cotransporter regulation by with-no-lysine kinases". American Journal of Physiology. Cell Physiology. 308 (10): C779–791. doi:10.1152/ajpcell.00065.2015. ISSN 1522-1563. PMC 4436992. PMID 25788573.{{cite journal}}: CS1 maint: PMC format (link)
  4. ^ a b c d e f g h i j k l m Xu, Bing E.; Lee, Byung Hoon; Min, Xiaoshan; Lenertz, Lisa; Heise, Charles J.; Stippec, Steve; Goldsmith, Elizabeth J.; Cobb, Melanie H. (January 2005). "WNK1: analysis of protein kinase structure, downstream targets, and potential roles in hypertension". Cell Research. 15 (1): 6–10. doi:10.1038/sj.cr.7290256. ISSN 1001-0602. PMID 15686619.
  5. ^ a b c d e f g h i j k l Huang, Chou-Long; Cheng, Chih-Jen (November 2015). "A unifying mechanism for WNK kinase regulation of sodium-chloride cotransporter". Pflugers Archiv: European Journal of Physiology. 467 (11): 2235–2241. doi:10.1007/s00424-015-1708-2. ISSN 1432-2013. PMC 4601926. PMID 25904388.{{cite journal}}: CS1 maint: PMC format (link)
  6. ^ a b Alessi, Dario R.; Zhang, Jinwei; Khanna, Arjun; Hochdörfer, Thomas; Shang, Yuze; Kahle, Kristopher T. (2014-07-15). "The WNK-SPAK/OSR1 pathway: master regulator of cation-chloride cotransporters". Science Signaling. 7 (334): re3. doi:10.1126/scisignal.2005365. ISSN 1937-9145. PMID 25028718.
  7. ^ Tang, Bor Luen. "(WNK)ing at death: With-no-lysine (Wnk) kinases in neuropathies and neuronal survival". Brain Research Bulletin. 125: 92–98. doi:10.1016/j.brainresbull.2016.04.017.