ID WNK4_HUMAN Reviewed; 1243 AA.
AC Q96J92; B0LPI0; Q8N8X3; Q8N8Z2; Q96DT8; Q9BYS5;
DT 02-FEB-2004, integrated into UniProtKB/Swiss-Prot.
DT 01-DEC-2001, sequence version 1.
DT 27-MAR-2024, entry version 192.
DE RecName: Full=Serine/threonine-protein kinase WNK4 {ECO:0000305};
DE EC=2.7.11.1 {ECO:0000269|PubMed:16832045};
DE AltName: Full=Protein kinase lysine-deficient 4 {ECO:0000312|HGNC:HGNC:14544};
DE AltName: Full=Protein kinase with no lysine 4 {ECO:0000303|PubMed:11571656};
GN Name=WNK4 {ECO:0000303|PubMed:11571656, ECO:0000312|HGNC:HGNC:14544};
GN Synonyms=PRKWNK4 {ECO:0000312|HGNC:HGNC:14544};
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606 {ECO:0000312|EMBL:AAK91995.1};
RN [1] {ECO:0000305}
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), DISEASE, AND VARIANTS PHA2B
RP LYS-562; ALA-564; GLU-565 AND CYS-1185.
RC TISSUE=Kidney {ECO:0000312|EMBL:AAK91995.1};
RX PubMed=11498583; DOI=10.1126/science.1062844;
RA Wilson F.H., Disse-Nicodeme S., Choate K.A., Ishikawa K.,
RA Nelson-Williams C., Desitter I., Gunel M., Milford D.V., Lipkin G.W.,
RA Achard J.-M., Feely M.P., Dussol B., Berland Y., Unwin R.J., Mayan H.,
RA Simon D.B., Farfel Z., Jeunemaitre X., Lifton R.P.;
RT "Human hypertension caused by mutations in WNK kinases.";
RL Science 293:1107-1112(2001).
RN [2] {ECO:0000305}
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Kidney {ECO:0000312|EMBL:CAC48387.1};
RA Chistiakov D.A.;
RL Thesis (2001), College de France / Paris, France.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2), AND NUCLEOTIDE SEQUENCE
RP [LARGE SCALE MRNA] OF 504-1165 (ISOFORM 3).
RC TISSUE=Kidney;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [4] {ECO:0000305}
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RG NHLBI resequencing and genotyping service (RS&G);
RL Submitted (DEC-2007) to the EMBL/GenBank/DDBJ databases.
RN [5] {ECO:0000305}
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [7] {ECO:0000305}
RP NUCLEOTIDE SEQUENCE [MRNA] OF 207-418 (ISOFORMS 1/3), TISSUE SPECIFICITY,
RP AND CHROMOSOMAL LOCATION.
RC TISSUE=Colon {ECO:0000312|EMBL:CAC32991.1};
RX PubMed=11571656; DOI=10.1038/sj.onc.1204726;
RA Verissimo F., Jordan P.;
RT "WNK kinases, a novel protein kinase subfamily in multi-cellular
RT organisms.";
RL Oncogene 20:5562-5569(2001).
RN [8]
RP DOMAIN, AND MUTAGENESIS OF ARG-1016; PHE-1017 AND VAL-1019.
RX PubMed=16669787; DOI=10.1042/bj20060220;
RA Vitari A.C., Thastrup J., Rafiqi F.H., Deak M., Morrice N.A.,
RA Karlsson H.K., Alessi D.R.;
RT "Functional interactions of the SPAK/OSR1 kinases with their upstream
RT activator WNK1 and downstream substrate NKCC1.";
RL Biochem. J. 397:223-231(2006).
RN [9]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=16832045; DOI=10.1073/pnas.0604607103;
RA Anselmo A.N., Earnest S., Chen W., Juang Y.C., Kim S.C., Zhao Y.,
RA Cobb M.H.;
RT "WNK1 and OSR1 regulate the Na+, K+, 2Cl- cotransporter in HeLa cells.";
RL Proc. Natl. Acad. Sci. U.S.A. 103:10883-10888(2006).
RN [10]
RP FUNCTION.
RX PubMed=20525693; DOI=10.1074/jbc.m110.103432;
RA Heise C.J., Xu B.E., Deaton S.L., Cha S.K., Cheng C.J., Earnest S.,
RA Sengupta S., Juang Y.C., Stippec S., Xu Y., Zhao Y., Huang C.L., Cobb M.H.;
RT "Serum and glucocorticoid-induced kinase (SGK) 1 and the epithelial sodium
RT channel are regulated by multiple with no lysine (WNK) family members.";
RL J. Biol. Chem. 285:25161-25167(2010).
RN [11]
RP FUNCTION.
RX PubMed=22989884; DOI=10.1074/jbc.m112.398750;
RA Sengupta S., Tu S.W., Wedin K., Earnest S., Stippec S., Luby-Phelps K.,
RA Cobb M.H.;
RT "Interactions with WNK (with no lysine) family members regulate oxidative
RT stress response 1 and ion co-transporter activity.";
RL J. Biol. Chem. 287:37868-37879(2012).
RN [12]
RP UBIQUITINATION BY KLHL2.
RX PubMed=23838290; DOI=10.1016/j.bbrc.2013.06.104;
RA Takahashi D., Mori T., Wakabayashi M., Mori Y., Susa K., Zeniya M.,
RA Sohara E., Rai T., Sasaki S., Uchida S.;
RT "KLHL2 interacts with and ubiquitinates WNK kinases.";
RL Biochem. Biophys. Res. Commun. 437:457-462(2013).
RN [13]
RP UBIQUITINATION, AND CHARACTERIZATION OF VARIANTS PHA2B LYS-562 AND GLU-565.
RX PubMed=23387299; DOI=10.1042/bj20121903;
RA Ohta A., Schumacher F.R., Mehellou Y., Johnson C., Knebel A.,
RA Macartney T.J., Wood N.T., Alessi D.R., Kurz T.;
RT "The CUL3-KLHL3 E3 ligase complex mutated in Gordon's hypertension syndrome
RT interacts with and ubiquitylates WNK isoforms: disease-causing mutations in
RT KLHL3 and WNK4 disrupt interaction.";
RL Biochem. J. 451:111-122(2013).
RN [14]
RP UBIQUITINATION, AND CHARACTERIZATION OF VARIANT PHA2B ALA-564.
RX PubMed=23453970; DOI=10.1016/j.celrep.2013.02.024;
RA Wakabayashi M., Mori T., Isobe K., Sohara E., Susa K., Araki Y., Chiga M.,
RA Kikuchi E., Nomura N., Mori Y., Matsuo H., Murata T., Nomura S., Asano T.,
RA Kawaguchi H., Nonoyama S., Rai T., Sasaki S., Uchida S.;
RT "Impaired KLHL3-mediated ubiquitination of WNK4 causes human
RT hypertension.";
RL Cell Rep. 3:858-868(2013).
RN [15]
RP UBIQUITINATION.
RX PubMed=23665031; DOI=10.1016/j.febslet.2013.04.032;
RA Wu G., Peng J.B.;
RT "Disease-causing mutations in KLHL3 impair its effect on WNK4
RT degradation.";
RL FEBS Lett. 587:1717-1722(2013).
RN [16]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-97, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Erythroleukemia;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
RN [17]
RP UBIQUITINATION AT LYS-157; LYS-175; LYS-186; LYS-226; LYS-241; LYS-328;
RP LYS-387; LYS-393; LYS-450; LYS-454; LYS-1010; LYS-1144; LYS-1157 AND
RP LYS-1158, AND CHARACTERIZATION OF VARIANTS PHA2B LYS-562 AND GLU-565.
RX PubMed=23576762; DOI=10.1073/pnas.1304592110;
RA Shibata S., Zhang J., Puthumana J., Stone K.L., Lifton R.P.;
RT "Kelch-like 3 and Cullin 3 regulate electrolyte homeostasis via
RT ubiquitination and degradation of WNK4.";
RL Proc. Natl. Acad. Sci. U.S.A. 110:7838-7843(2013).
RN [18]
RP UBIQUITINATION.
RX PubMed=26435498; DOI=10.1016/j.bbrc.2015.09.184;
RA Yoshizaki Y., Mori Y., Tsuzaki Y., Mori T., Nomura N., Wakabayashi M.,
RA Takahashi D., Zeniya M., Kikuchi E., Araki Y., Ando F., Isobe K.,
RA Nishida H., Ohta A., Susa K., Inoue Y., Chiga M., Rai T., Sasaki S.,
RA Uchida S., Sohara E.;
RT "Impaired degradation of WNK by Akt and PKA phosphorylation of KLHL3.";
RL Biochem. Biophys. Res. Commun. 467:229-234(2015).
RN [19]
RP PHOSPHORYLATION AT SER-575, AND MUTAGENESIS OF SER-575.
RX PubMed=26732173; DOI=10.1038/srep18710;
RA Maruyama J., Kobayashi Y., Umeda T., Vandewalle A., Takeda K., Ichijo H.,
RA Naguro I.;
RT "Osmotic stress induces the phosphorylation of WNK4 Ser575 via the p38MAPK-
RT MK pathway.";
RL Sci. Rep. 6:18710-18710(2016).
RN [20]
RP UBIQUITINATION.
RX PubMed=27727489; DOI=10.1002/pro.3063;
RA Wang L., Peng J.B.;
RT "Phosphorylation of KLHL3 at serine 433 impairs its interaction with the
RT acidic motif of WNK4: a molecular dynamics study.";
RL Protein Sci. 26:163-173(2017).
RN [21] {ECO:0007744|PDB:2V3S}
RP X-RAY CRYSTALLOGRAPHY (1.70 ANGSTROMS) OF 1015-1020 IN COMPLEX WITH OXSR1,
RP AND DOMAIN.
RX PubMed=17721439; DOI=10.1038/sj.embor.7401048;
RA Villa F., Goebel J., Rafiqi F.H., Deak M., Thastrup J., Alessi D.R.,
RA van Aalten D.M.;
RT "Structural insights into the recognition of substrates and activators by
RT the OSR1 kinase.";
RL EMBO Rep. 8:839-845(2007).
RN [22] {ECO:0007744|PDB:4CH9, ECO:0007744|PDB:4CHB}
RP X-RAY CRYSTALLOGRAPHY (1.56 ANGSTROMS) OF 557-567 IN COMPLEX WITH KLHL2 AND
RP KLHL3, UBIQUITINATION, AND CHARACTERIZATION OF VARIANTS PHA2B ALA-564 AND
RP GLU-565.
RX PubMed=24641320; DOI=10.1042/bj20140153;
RA Schumacher F.R., Sorrell F.J., Alessi D.R., Bullock A.N., Kurz T.;
RT "Structural and biochemical characterization of the KLHL3-WNK kinase
RT interaction important in blood pressure regulation.";
RL Biochem. J. 460:237-246(2014).
RN [23]
RP VARIANTS [LARGE SCALE ANALYSIS] ASP-434; LEU-813; SER-992 AND PRO-1013.
RX PubMed=17344846; DOI=10.1038/nature05610;
RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G.,
RA Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S.,
RA Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G.,
RA Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K.,
RA Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D.,
RA Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R.,
RA Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A.,
RA Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F.,
RA Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F.,
RA Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G.,
RA Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R.,
RA Futreal P.A., Stratton M.R.;
RT "Patterns of somatic mutation in human cancer genomes.";
RL Nature 446:153-158(2007).
CC -!- FUNCTION: Serine/threonine-protein kinase component of the WNK4-
CC SPAK/OSR1 kinase cascade, which acts as a key regulator of ion
CC transport in the distal nephron and blood pressure (By similarity). The
CC WNK4-SPAK/OSR1 kinase cascade is composed of WNK4, which mediates
CC phosphorylation and activation of downstream kinases OXSR1/OSR1 and
CC STK39/SPAK (PubMed:16832045). Following activation, OXSR1/OSR1 and
CC STK39/SPAK catalyze phosphorylation of ion cotransporters, such as
CC SLC12A1/NKCC2, SLC12A2/NKCC1, SLC12A3/NCC, SLC12A5/KCC2 or
CC SLC12A6/KCC3, regulating their activity (PubMed:16832045,
CC PubMed:22989884). Acts as a molecular switch that regulates the balance
CC between renal salt reabsorption and K(+) secretion by modulating the
CC activities of renal transporters and channels, including the Na-Cl
CC cotransporter SLC12A3/NCC and the K(+) channel, KCNJ1/ROMK (By
CC similarity). Regulates NaCl reabsorption in the distal nephron by
CC activating the thiazide-sensitive Na-Cl cotransporter SLC12A3/NCC in
CC distal convoluted tubule cells of kidney: activates SLC12A3/NCC in a
CC OXSR1/OSR1- and STK39/SPAK-dependent process (By similarity). Also acts
CC as a scaffold protein independently of its protein kinase activity:
CC negatively regulates cell membrane localization of various transporters
CC and channels (CFTR, KCNJ1/ROMK, SLC4A4, SLC26A9 and TRPV4) by clathrin-
CC dependent endocytosis (By similarity). Also inhbits the activity of the
CC epithelial Na(+) channel (ENaC) SCNN1A, SCNN1B, SCNN1D in a inase-
CC independent mechanism (By similarity). May also phosphorylate NEDD4L
CC (PubMed:20525693). {ECO:0000250|UniProtKB:Q80UE6,
CC ECO:0000269|PubMed:16832045, ECO:0000269|PubMed:20525693,
CC ECO:0000269|PubMed:22989884}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-
CC [protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA-
CC COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616,
CC ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.1;
CC Evidence={ECO:0000250|UniProtKB:Q9H4A3};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L-
CC threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060,
CC Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013,
CC ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216;
CC EC=2.7.11.1; Evidence={ECO:0000269|PubMed:16832045};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000250|UniProtKB:Q9H4A3};
CC -!- ACTIVITY REGULATION: Activation requires autophosphorylation of Ser-331
CC and Ser-335 (By similarity). Autophosphorylation and subsequent
CC activation is inhibited by increases in intracellular ionic strength:
CC Cl(-) potently inhibits WNK4 kinase activity via direct binding (By
CC similarity). Also inhibited by K(+) ions (By similarity).
CC {ECO:0000250|UniProtKB:Q80UE6, ECO:0000250|UniProtKB:Q9JIH7}.
CC -!- SUBUNIT: Interacts with the C-terminal region of KCNJ1.
CC {ECO:0000250|UniProtKB:Q80UE6}.
CC -!- INTERACTION:
CC Q96J92; O95747: OXSR1; NbExp=12; IntAct=EBI-766352, EBI-620853;
CC Q96J92; P62258: YWHAE; NbExp=2; IntAct=EBI-766352, EBI-356498;
CC -!- SUBCELLULAR LOCATION: Cell junction, tight junction
CC {ECO:0000250|UniProtKB:Q80UE6}. Note=Present exclusively in
CC intercellular junctions in the distal convoluted tubule and in both the
CC cytoplasm and intercellular junctions in the cortical collecting duct
CC (By similarity). WNK4 is part of the tight junction complex (By
CC similarity). {ECO:0000250|UniProtKB:Q80UE6}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1 {ECO:0000269|PubMed:11498583, ECO:0000305};
CC IsoId=Q96J92-1; Sequence=Displayed;
CC Name=2 {ECO:0000305};
CC IsoId=Q96J92-2; Sequence=VSP_050648, VSP_050649, VSP_050650,
CC VSP_050651;
CC Name=3 {ECO:0000305};
CC IsoId=Q96J92-3; Sequence=VSP_050652, VSP_050653;
CC -!- TISSUE SPECIFICITY: Expressed in kidney, colon and skin.
CC {ECO:0000269|PubMed:11571656}.
CC -!- DOMAIN: The RFXV motif mediates recognition with downstream kinases
CC OXSR1/OSR1 and STK39/SPAK. {ECO:0000269|PubMed:16669787,
CC ECO:0000269|PubMed:24641320}.
CC -!- PTM: Autophosphorylated at Ser-331 and Ser-335, promoting its
CC activation (By similarity). Phosphorylated by WNK1 and WNK3 (By
CC similarity). Phosphorylated at Ser-575 in a MAP3K15/ASK3-dependent
CC process in response to osmotic stress or hypotonic low-chloride
CC stimulation (PubMed:26732173). {ECO:0000250|UniProtKB:Q80UE6,
CC ECO:0000250|UniProtKB:Q9JIH7, ECO:0000269|PubMed:26732173}.
CC -!- PTM: Ubiquitinated by the BCR(KLHL3) complex, leading to its
CC degradation (PubMed:23387299, PubMed:23453970, PubMed:23665031,
CC PubMed:23576762, PubMed:26435498, PubMed:27727489, PubMed:24641320).
CC Also ubiquitinated by the BCR(KLHL2) complex (PubMed:23838290,
CC PubMed:24641320). {ECO:0000269|PubMed:23387299,
CC ECO:0000269|PubMed:23453970, ECO:0000269|PubMed:23576762,
CC ECO:0000269|PubMed:23665031, ECO:0000269|PubMed:23838290,
CC ECO:0000269|PubMed:24641320, ECO:0000269|PubMed:26435498,
CC ECO:0000269|PubMed:27727489}.
CC -!- DISEASE: Pseudohypoaldosteronism 2B (PHA2B) [MIM:614491]: An autosomal
CC dominant disorder characterized by hypertension, hyperkalemia,
CC hyperchloremia, mild hyperchloremic metabolic acidosis, and correction
CC of physiologic abnormalities by thiazide diuretics.
CC {ECO:0000269|PubMed:11498583, ECO:0000269|PubMed:23387299,
CC ECO:0000269|PubMed:23453970, ECO:0000269|PubMed:23576762,
CC ECO:0000269|PubMed:24641320}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- MISCELLANEOUS: [Isoform 3]: Incomplete sequence. {ECO:0000305}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. Ser/Thr protein
CC kinase family. WNK subfamily. {ECO:0000255|PROSITE-ProRule:PRU00159}.
CC -!- CAUTION: Was named WNK/'with no lysine(K)' because key residues for
CC catalysis, including the lysine involved in ATP binding, are either not
CC conserved or differ compared to the residues described in other kinase
CC family proteins. {ECO:0000250|UniProtKB:Q9H4A3}.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAC04669.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
CC Sequence=CAC48387.1; Type=Frameshift; Evidence={ECO:0000305};
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DR EMBL; AF390018; AAK91995.1; -; mRNA.
DR EMBL; AJ316534; CAC48387.1; ALT_FRAME; mRNA.
DR EMBL; AK096003; BAC04669.1; ALT_INIT; mRNA.
DR EMBL; AK096052; BAC04688.1; -; mRNA.
DR EMBL; EU332870; ABY87559.1; -; Genomic_DNA.
DR EMBL; CH471152; EAW60881.1; -; Genomic_DNA.
DR EMBL; CH471152; EAW60882.1; -; Genomic_DNA.
DR EMBL; BC136664; AAI36665.1; -; mRNA.
DR EMBL; AJ309861; CAC32991.1; -; mRNA.
DR CCDS; CCDS11439.1; -. [Q96J92-1]
DR RefSeq; NP_115763.2; NM_032387.4. [Q96J92-1]
DR PDB; 2V3S; X-ray; 1.70 A; C/D=1015-1020.
DR PDB; 4CH9; X-ray; 1.84 A; C/D=557-567.
DR PDB; 4CHB; X-ray; 1.56 A; C/D=557-567.
DR PDBsum; 2V3S; -.
DR PDBsum; 4CH9; -.
DR PDBsum; 4CHB; -.
DR AlphaFoldDB; Q96J92; -.
DR SMR; Q96J92; -.
DR BioGRID; 122421; 16.
DR CORUM; Q96J92; -.
DR ELM; Q96J92; -.
DR IntAct; Q96J92; 9.
DR MINT; Q96J92; -.
DR STRING; 9606.ENSP00000246914; -.
DR BindingDB; Q96J92; -.
DR ChEMBL; CHEMBL1795196; -.
DR TCDB; 8.A.23.1.50; the basigin (basigin) family.
DR GlyGen; Q96J92; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; Q96J92; -.
DR PhosphoSitePlus; Q96J92; -.
DR BioMuta; WNK4; -.
DR DMDM; 41688789; -.
DR EPD; Q96J92; -.
DR jPOST; Q96J92; -.
DR MassIVE; Q96J92; -.
DR MaxQB; Q96J92; -.
DR PaxDb; 9606-ENSP00000246914; -.
DR PeptideAtlas; Q96J92; -.
DR ProteomicsDB; 76909; -. [Q96J92-1]
DR ProteomicsDB; 76910; -. [Q96J92-2]
DR ProteomicsDB; 76911; -. [Q96J92-3]
DR Pumba; Q96J92; -.
DR Antibodypedia; 29411; 262 antibodies from 26 providers.
DR DNASU; 65266; -.
DR Ensembl; ENST00000246914.10; ENSP00000246914.4; ENSG00000126562.17. [Q96J92-1]
DR GeneID; 65266; -.
DR KEGG; hsa:65266; -.
DR MANE-Select; ENST00000246914.10; ENSP00000246914.4; NM_032387.5; NP_115763.2.
DR UCSC; uc002ibj.4; human. [Q96J92-1]
DR AGR; HGNC:14544; -.
DR CTD; 65266; -.
DR DisGeNET; 65266; -.
DR GeneCards; WNK4; -.
DR GeneReviews; WNK4; -.
DR HGNC; HGNC:14544; WNK4.
DR HPA; ENSG00000126562; Tissue enhanced (intestine, kidney, prostate).
DR MalaCards; WNK4; -.
DR MIM; 601844; gene.
DR MIM; 614491; phenotype.
DR neXtProt; NX_Q96J92; -.
DR OpenTargets; ENSG00000126562; -.
DR Orphanet; 88939; Pseudohypoaldosteronism type 2B.
DR PharmGKB; PA134875400; -.
DR VEuPathDB; HostDB:ENSG00000126562; -.
DR eggNOG; KOG0584; Eukaryota.
DR GeneTree; ENSGT00940000159871; -.
DR HOGENOM; CLU_000550_2_1_1; -.
DR InParanoid; Q96J92; -.
DR OMA; HHPASMF; -.
DR OrthoDB; 5478852at2759; -.
DR PhylomeDB; Q96J92; -.
DR TreeFam; TF315363; -.
DR PathwayCommons; Q96J92; -.
DR Reactome; R-HSA-2672351; Stimuli-sensing channels.
DR SignaLink; Q96J92; -.
DR SIGNOR; Q96J92; -.
DR BioGRID-ORCS; 65266; 25 hits in 1194 CRISPR screens.
DR ChiTaRS; WNK4; human.
DR EvolutionaryTrace; Q96J92; -.
DR GeneWiki; WNK4; -.
DR GenomeRNAi; 65266; -.
DR Pharos; Q96J92; Tbio.
DR PRO; PR:Q96J92; -.
DR Proteomes; UP000005640; Chromosome 17.
DR RNAct; Q96J92; Protein.
DR Bgee; ENSG00000126562; Expressed in kidney epithelium and 118 other cell types or tissues.
DR ExpressionAtlas; Q96J92; baseline and differential.
DR Genevisible; Q96J92; HS.
DR GO; GO:0005923; C:bicellular tight junction; ISS:UniProtKB.
DR GO; GO:0044297; C:cell body; IEA:Ensembl.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR GO; GO:0005829; C:cytosol; ISS:ParkinsonsUK-UCL.
DR GO; GO:0016020; C:membrane; ISS:ParkinsonsUK-UCL.
DR GO; GO:0032991; C:protein-containing complex; IEA:Ensembl.
DR GO; GO:0005524; F:ATP binding; ISS:UniProtKB.
DR GO; GO:0031404; F:chloride ion binding; IEA:Ensembl.
DR GO; GO:0008200; F:ion channel inhibitor activity; ISS:UniProtKB.
DR GO; GO:0004672; F:protein kinase activity; IBA:GO_Central.
DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; IDA:UniProt.
DR GO; GO:0035932; P:aldosterone secretion; IEA:Ensembl.
DR GO; GO:0055074; P:calcium ion homeostasis; IEA:Ensembl.
DR GO; GO:0071466; P:cellular response to xenobiotic stimulus; IEA:Ensembl.
DR GO; GO:0006821; P:chloride transport; IEA:Ensembl.
DR GO; GO:0072156; P:distal tubule morphogenesis; IMP:UniProtKB.
DR GO; GO:0070371; P:ERK1 and ERK2 cascade; IEA:Ensembl.
DR GO; GO:0010467; P:gene expression; IEA:Ensembl.
DR GO; GO:0006954; P:inflammatory response; IEA:Ensembl.
DR GO; GO:0030644; P:intracellular chloride ion homeostasis; IEA:Ensembl.
DR GO; GO:0035556; P:intracellular signal transduction; ISS:UniProtKB.
DR GO; GO:0042116; P:macrophage activation; IEA:Ensembl.
DR GO; GO:0050801; P:monoatomic ion homeostasis; IMP:UniProtKB.
DR GO; GO:0090188; P:negative regulation of pancreatic juice secretion; IEA:Ensembl.
DR GO; GO:1903077; P:negative regulation of protein localization to plasma membrane; ISS:UniProtKB.
DR GO; GO:0010766; P:negative regulation of sodium ion transport; ISS:UniProtKB.
DR GO; GO:0071805; P:potassium ion transmembrane transport; IEA:Ensembl.
DR GO; GO:0070528; P:protein kinase C signaling; IEA:Ensembl.
DR GO; GO:0008104; P:protein localization; IEA:Ensembl.
DR GO; GO:0006468; P:protein phosphorylation; ISS:UniProtKB.
DR GO; GO:0008217; P:regulation of blood pressure; IEA:Ensembl.
DR GO; GO:1903764; P:regulation of potassium ion export across plasma membrane; IEA:Ensembl.
DR GO; GO:0070294; P:renal sodium ion absorption; IMP:UniProtKB.
DR GO; GO:0003096; P:renal sodium ion transport; ISS:UniProtKB.
DR GO; GO:0002021; P:response to dietary excess; IEA:Ensembl.
DR GO; GO:0007165; P:signal transduction; IBA:GO_Central.
DR GO; GO:0035725; P:sodium ion transmembrane transport; IEA:Ensembl.
DR CDD; cd14033; STKc_WNK4; 1.
DR Gene3D; 1.10.510.10; Transferase(Phosphotransferase) domain 1; 1.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR024678; Kinase_OSR1/WNK_CCT.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR008271; Ser/Thr_kinase_AS.
DR PANTHER; PTHR13902; SERINE/THREONINE-PROTEIN KINASE WNK WITH NO LYSINE -RELATED; 1.
DR PANTHER; PTHR13902:SF114; SERINE_THREONINE-PROTEIN KINASE WNK4; 1.
DR Pfam; PF12202; OSR1_C; 1.
DR Pfam; PF00069; Pkinase; 1.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF56112; Protein kinase-like (PK-like); 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; ATP-binding; Cell junction;
KW Disease variant; Isopeptide bond; Kinase; Nucleotide-binding;
KW Phosphoprotein; Reference proteome; Serine/threonine-protein kinase;
KW Tight junction; Transferase; Ubl conjugation.
FT CHAIN 1..1243
FT /note="Serine/threonine-protein kinase WNK4"
FT /id="PRO_0000086824"
FT DOMAIN 174..432
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REGION 1..142
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 526..564
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 557..567
FT /note="Interaction with KLHL3"
FT /evidence="ECO:0000269|PubMed:24641320"
FT REGION 630..683
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 751..871
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 943..1110
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1166..1243
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 1016..1019
FT /note="RFXV motif"
FT /evidence="ECO:0000269|PubMed:16669787,
FT ECO:0000269|PubMed:24641320"
FT COMPBIAS 1..16
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 44..60
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 77..105
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 533..558
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 782..811
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 812..842
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 949..974
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1038..1060
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1068..1093
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1186..1204
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1215..1232
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 321
FT /note="Proton acceptor"
FT /evidence="ECO:0000250|UniProtKB:Q9JIH7"
FT BINDING 184
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:Q9H4A3"
FT BINDING 254..257
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:Q9H4A3"
FT BINDING 304
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:Q9H4A3"
FT MOD_RES 97
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 331
FT /note="Phosphoserine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:Q9JIH7"
FT MOD_RES 335
FT /note="Phosphoserine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:Q9JIH7"
FT MOD_RES 575
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:26732173"
FT MOD_RES 1035
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q7TPK6"
FT MOD_RES 1217
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q80UE6"
FT CROSSLNK 157
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000269|PubMed:23576762"
FT CROSSLNK 175
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000269|PubMed:23576762"
FT CROSSLNK 186
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000269|PubMed:23576762"
FT CROSSLNK 226
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000269|PubMed:23576762"
FT CROSSLNK 241
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000269|PubMed:23576762"
FT CROSSLNK 328
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000269|PubMed:23576762"
FT CROSSLNK 387
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000269|PubMed:23576762"
FT CROSSLNK 393
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000269|PubMed:23576762"
FT CROSSLNK 450
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000269|PubMed:23576762"
FT CROSSLNK 454
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000269|PubMed:23576762"
FT CROSSLNK 1010
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000269|PubMed:23576762"
FT CROSSLNK 1144
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000269|PubMed:23576762"
FT CROSSLNK 1157
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000269|PubMed:23576762"
FT CROSSLNK 1158
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000269|PubMed:23576762"
FT VAR_SEQ 1..228
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_050648"
FT VAR_SEQ 229..264
FT /note="QHPNIVRFYDSWKSVLRGQVCIVLVTELMTSGTLKT -> MRRRQQGAAGGN
FT FPVGGSFPEDVSPHQDSGYAPSPR (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_050649"
FT VAR_SEQ 828..1210
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_050650"
FT VAR_SEQ 1145..1165
FT /note="HLSEVETLQTLQKKEIEDLYS -> PFHALRASSGTCQRWKHYRHY (in
FT isoform 3)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_050652"
FT VAR_SEQ 1166..1243
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_050653"
FT VAR_SEQ 1233..1243
FT /note="GVTFAGDVGRM -> EAGQRPGKLWLRATVQLRVWGLELRRKEMMGRNPKLG
FT AAPNP (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_050651"
FT VARIANT 434
FT /note="E -> D (in an ovarian mucinous carcinoma sample;
FT somatic mutation)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_041330"
FT VARIANT 562
FT /note="E -> K (in PHA2B; impaired interaction with KLHL3;
FT dbSNP:rs137853093)"
FT /evidence="ECO:0000269|PubMed:11498583,
FT ECO:0000269|PubMed:23387299, ECO:0000269|PubMed:23576762"
FT /id="VAR_017588"
FT VARIANT 564
FT /note="D -> A (in PHA2B; impaired interaction with KLHL3;
FT dbSNP:rs137853094)"
FT /evidence="ECO:0000269|PubMed:11498583,
FT ECO:0000269|PubMed:23453970, ECO:0000269|PubMed:24641320"
FT /id="VAR_017589"
FT VARIANT 565
FT /note="Q -> E (in PHA2B; impaired interaction with KLHL3;
FT dbSNP:rs137853092)"
FT /evidence="ECO:0000269|PubMed:11498583,
FT ECO:0000269|PubMed:23387299, ECO:0000269|PubMed:23576762,
FT ECO:0000269|PubMed:24641320"
FT /id="VAR_017590"
FT VARIANT 601
FT /note="A -> S (in dbSNP:rs55781437)"
FT /id="VAR_061748"
FT VARIANT 677
FT /note="R -> W (in dbSNP:rs9896991)"
FT /id="VAR_051685"
FT VARIANT 813
FT /note="P -> L"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_041331"
FT VARIANT 961
FT /note="P -> S (in dbSNP:rs2290041)"
FT /id="VAR_051686"
FT VARIANT 992
FT /note="P -> S (in a metastatic melanoma sample; somatic
FT mutation)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_041332"
FT VARIANT 1013
FT /note="L -> P"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_041333"
FT VARIANT 1185
FT /note="R -> C (in PHA2B; dbSNP:rs137853095)"
FT /evidence="ECO:0000269|PubMed:11498583"
FT /id="VAR_017591"
FT MUTAGEN 575
FT /note="S->A: Abolished MAP3K15/ASK3-dependent
FT phosphorylation."
FT /evidence="ECO:0000269|PubMed:26732173"
FT MUTAGEN 575
FT /note="S->E,D: Mimics phosphorylation without affecting
FT WNK4 kinase activity."
FT /evidence="ECO:0000269|PubMed:26732173"
FT MUTAGEN 1016
FT /note="R->A: Abolished interaction with OXSR1/OSR1."
FT /evidence="ECO:0000269|PubMed:16669787"
FT MUTAGEN 1017
FT /note="F->A: Abolished interaction with OXSR1/OSR1."
FT /evidence="ECO:0000269|PubMed:16669787"
FT MUTAGEN 1019
FT /note="V->A: Abolished interaction with OXSR1/OSR1."
FT /evidence="ECO:0000269|PubMed:16669787"
FT CONFLICT 525
FT /note="R -> C (in Ref. 3; BAC04688)"
FT /evidence="ECO:0000305"
FT HELIX 562..564
FT /evidence="ECO:0007829|PDB:4CHB"
SQ SEQUENCE 1243 AA; 134739 MW; BAC35F0098BA3391 CRC64;
MLASPATETT VLMSQTEADL ALRPPPPLGT AGQPRLGPPP RRARRFSGKA EPRPRSSRLS
RRSSVDLGLL SSWSLPASPA PDPPDPPDSA GPGPARSPPP SSKEPPEGTW TEGAPVKAAE
DSARPELPDS AVGPGSREPL RVPEAVALER RREQEEKEDM ETQAVATSPD GRYLKFDIEI
GRGSFKTVYR GLDTDTTVEV AWCELQTRKL SRAERQRFSE EVEMLKGLQH PNIVRFYDSW
KSVLRGQVCI VLVTELMTSG TLKTYLRRFR EMKPRVLQRW SRQILRGLHF LHSRVPPILH
RDLKCDNVFI TGPTGSVKIG DLGLATLKRA SFAKSVIGTP EFMAPEMYEE KYDEAVDVYA
FGMCMLEMAT SEYPYSECQN AAQIYRKVTS GRKPNSFHKV KIPEVKEIIE GCIRTDKNER
FTIQDLLAHA FFREERGVHV ELAEEDDGEK PGLKLWLRME DARRGGRPRD NQAIEFLFQL
GRDAAEEVAQ EMVALGLVCE ADYQPVARAV RERVAAIQRK REKLRKAREL EALPPEPGPP
PATVPMAPGP PSVFPPEPEE PEADQHQPFL FRHASYSSTT SDCETDGYLS SSGFLDASDP
ALQPPGGVPS SLAESHLCLP SAFALSIPRS GPGSDFSPGD SYASDAASGL SDVGEGMGQM
RRPPGRNLRR RPRSRLRVTS VSDQNDRVVE CQLQTHNSKM VTFRFDLDGD SPEEIAAAMV
YNEFILPSER DGFLRRIREI IQRVETLLKR DTGPMEAAED TLSPQEEPAP LPALPVPLPD
PSNEELQSST SLEHRSWTAF STSSSSPGTP LSPGNPFSPG TPISPGPIFP ITSPPCHPSP
SPFSPISSQV SSNPSPHPTS SPLPFSSSTP EFPVPLSQCP WSSLPTTSPP TFSPTCSQVT
LSSPFFPPCP STSSFPSTTA APLLSLASAF SLAVMTVAQS LLSPSPGLLS QSPPAPPSPL
PSLPLPPPVA PGGQESPSPH TAEVESEASP PPARPLPGEA RLAPISEEGK PQLVGRFQVT
SSKEPAEPLP LQPTSPTLSG SPKPSTPQLT SESSDTEDSA GGGPETREAL AESDRAAEGL
GAGVEEEGDD GKEPQVGGSP QPLSHPSPVW MNYSYSSLCL SSEESESSGE DEEFWAELQS
LRQKHLSEVE TLQTLQKKEI EDLYSRLGKQ PPPGIVAPAA MLSSRQRRLS KGSFPTSRRN
SLQRSEPPGP GIMRRNSLSG SSTGSQEQRA SKGVTFAGDV GRM
//
