SPHK1_HUMAN
ID SPHK1_HUMAN Reviewed; 384 AA.
AC Q9NYA1; Q8N632; Q96GK1; Q9HD92; Q9NY70; Q9NYL3;
DT 24-OCT-2001, integrated into UniProtKB/Swiss-Prot.
DT 01-OCT-2000, sequence version 1.
DT 03-AUG-2022, entry version 185.
DE RecName: Full=Sphingosine kinase 1 {ECO:0000305};
DE Short=SK 1 {ECO:0000303|PubMed:23935096};
DE Short=SPK 1;
DE EC=2.7.1.91 {ECO:0000269|PubMed:10802064, ECO:0000269|PubMed:20577214, ECO:0000269|PubMed:23602659, ECO:0000269|PubMed:24929359};
DE AltName: Full=Acetyltransferase SPHK1;
DE EC=2.3.1.-;
GN Name=SPHK1 {ECO:0000312|HGNC:HGNC:11240};
GN Synonyms=SK1 {ECO:0000303|PubMed:23935096}, SPHK, SPK;
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;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=10863092; DOI=10.1016/s0378-1119(00)00205-5;
RA Melendez A.J., Carlos-Dias E., Gosink M., Allen J.M., Takacs L.;
RT "Human sphingosine kinase: molecular cloning, functional characterization
RT and tissue distribution.";
RL Gene 251:19-26(2000).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), CATALYTIC ACTIVITY, SUBSTRATE
RP SPECIFICITY, AND TISSUE SPECIFICITY.
RX PubMed=10802064; DOI=10.1016/s0014-5793(00)01510-6;
RA Nava V.E., Lacana' E., Poulton S., Liu H., Sugiura M., Kono K.,
RA Milstien S., Kohama T., Spiegel S.;
RT "Functional characterization of human sphingosine kinase-1.";
RL FEBS Lett. 473:81-84(2000).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), SUBSTRATE SPECIFICITY,
RP BIOPHYSICOCHEMICAL PROPERTIES, AND COFACTOR.
RX PubMed=10947957; DOI=10.1042/bj3500429;
RA Pitson S.M., D'Andrea R.J., Vandeleur L., Moretti P.A.B., Xia P.,
RA Gamble J.R., Vadas M.A., Wattenberg B.W.;
RT "Human sphingosine kinase: purification, molecular cloning and
RT characterization of the native and recombinant enzymes.";
RL Biochem. J. 350:429-441(2000).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RA Van Veldhoven P.P., Gijsbers S.;
RL Submitted (AUG-1999) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Mammary gland, Ovary, and Testis;
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 [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16625196; DOI=10.1038/nature04689;
RA Zody M.C., Garber M., Adams D.J., Sharpe T., Harrow J., Lupski J.R.,
RA Nicholson C., Searle S.M., Wilming L., Young S.K., Abouelleil A.,
RA Allen N.R., Bi W., Bloom T., Borowsky M.L., Bugalter B.E., Butler J.,
RA Chang J.L., Chen C.-K., Cook A., Corum B., Cuomo C.A., de Jong P.J.,
RA DeCaprio D., Dewar K., FitzGerald M., Gilbert J., Gibson R., Gnerre S.,
RA Goldstein S., Grafham D.V., Grocock R., Hafez N., Hagopian D.S., Hart E.,
RA Norman C.H., Humphray S., Jaffe D.B., Jones M., Kamal M., Khodiyar V.K.,
RA LaButti K., Laird G., Lehoczky J., Liu X., Lokyitsang T., Loveland J.,
RA Lui A., Macdonald P., Major J.E., Matthews L., Mauceli E., McCarroll S.A.,
RA Mihalev A.H., Mudge J., Nguyen C., Nicol R., O'Leary S.B., Osoegawa K.,
RA Schwartz D.C., Shaw-Smith C., Stankiewicz P., Steward C., Swarbreck D.,
RA Venkataraman V., Whittaker C.A., Yang X., Zimmer A.R., Bradley A.,
RA Hubbard T., Birren B.W., Rogers J., Lander E.S., Nusbaum C.;
RT "DNA sequence of human chromosome 17 and analysis of rearrangement in the
RT human lineage.";
RL Nature 440:1045-1049(2006).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.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 [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 2 AND 3).
RC TISSUE=Blood, Kidney, and Skin;
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 [9]
RP FUNCTION, CATALYTIC ACTIVITY, SUBSTRATE SPECIFICITY, AND BIOPHYSICOCHEMICAL
RP PROPERTIES.
RX PubMed=11923095; DOI=10.1016/s1388-1981(01)00166-4;
RA Gijsbers S., Asselberghs S., Herdewijn P., Van Veldhoven P.P.;
RT "1-O-Hexadecyl-2-desoxy-2-amino-sn-glycerol, a substrate for human
RT sphingosine kinase.";
RL Biochim. Biophys. Acta 1580:1-8(2002).
RN [10]
RP INTERACTION WITH SPHKAP.
RX PubMed=12080051; DOI=10.1074/jbc.m202841200;
RA Lacana E., Maceyka M., Milstien S., Spiegel S.;
RT "Cloning and characterization of a protein kinase A anchoring protein
RT (AKAP)-related protein that interacts with and regulates sphingosine kinase
RT 1 activity.";
RL J. Biol. Chem. 277:32947-32953(2002).
RN [11]
RP SUBCELLULAR LOCATION, AND NUCLEAR EXPORT SIGNALS.
RX PubMed=14575709; DOI=10.1016/j.bbrc.2003.09.194;
RA Inagaki Y., Li P.Y., Wada A., Mitsutake S., Igarashi Y.;
RT "Identification of functional nuclear export sequences in human sphingosine
RT kinase 1.";
RL Biochem. Biophys. Res. Commun. 311:168-173(2003).
RN [12]
RP FUNCTION.
RX PubMed=16118219; DOI=10.1074/jbc.m502207200;
RA Maceyka M., Sankala H., Hait N.C., Le Stunff H., Liu H., Toman R.,
RA Collier C., Zhang M., Satin L.S., Merrill A.H. Jr., Milstien S.,
RA Spiegel S.;
RT "SphK1 and SphK2, sphingosine kinase isoenzymes with opposing functions in
RT sphingolipid metabolism.";
RL J. Biol. Chem. 280:37118-37129(2005).
RN [13]
RP INTERACTION WITH EEF1A1, AND BIOPHYSICOCHEMICAL PROPERTIES.
RX PubMed=18263879; DOI=10.1074/jbc.m708782200;
RA Leclercq T.M., Moretti P.A., Vadas M.A., Pitson S.M.;
RT "Eukaryotic elongation factor 1A interacts with sphingosine kinase and
RT directly enhances its catalytic activity.";
RL J. Biol. Chem. 283:9606-9614(2008).
RN [14]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-193, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [15]
RP INTERACTION WITH CIB1, SUBCELLULAR LOCATION, AND MUTAGENESIS OF
RP 197-PHE-LEU-198.
RX PubMed=19854831; DOI=10.1074/jbc.m109.068395;
RA Jarman K.E., Moretti P.A., Zebol J.R., Pitson S.M.;
RT "Translocation of sphingosine kinase 1 to the plasma membrane is mediated
RT by calcium- and integrin-binding protein 1.";
RL J. Biol. Chem. 285:483-492(2010).
RN [16]
RP CATALYTIC ACTIVITY, FUNCTION, INTERACTION WITH TRAF2, MUTAGENESIS OF
RP GLY-82, AND PHOSPHORYLATION AT SER-225.
RX PubMed=20577214; DOI=10.1038/nature09128;
RA Alvarez S.E., Harikumar K.B., Hait N.C., Allegood J., Strub G.M., Kim E.Y.,
RA Maceyka M., Jiang H., Luo C., Kordula T., Milstien S., Spiegel S.;
RT "Sphingosine-1-phosphate is a missing cofactor for the E3 ubiquitin ligase
RT TRAF2.";
RL Nature 465:1084-1088(2010).
RN [17]
RP FUNCTION.
RX PubMed=23935096; DOI=10.1074/jbc.m113.489443;
RA Adada M.M., Orr-Gandy K.A., Snider A.J., Canals D., Hannun Y.A.,
RA Obeid L.M., Clarke C.J.;
RT "Sphingosine kinase 1 regulates tumor necrosis factor-mediated RANTES
RT induction through p38 mitogen-activated protein kinase but independently of
RT nuclear factor kappaB activation.";
RL J. Biol. Chem. 288:27667-27679(2013).
RN [18]
RP FUNCTION, SUBCELLULAR LOCATION, CATALYTIC ACTIVITY, AND MUTAGENESIS OF
RP LEU-194 AND 197-PHE-LEU-198.
RX PubMed=24929359; DOI=10.1038/ncb2987;
RA Shen H., Giordano F., Wu Y., Chan J., Zhu C., Milosevic I., Wu X., Yao K.,
RA Chen B., Baumgart T., Sieburth D., De Camilli P.;
RT "Coupling between endocytosis and sphingosine kinase 1 recruitment.";
RL Nat. Cell Biol. 16:652-662(2014).
RN [19]
RP FUNCTION, ACTIVITY REGULATION, AND CATALYTIC ACTIVITY.
RX PubMed=25417698; DOI=10.1038/ncomms6514;
RA Lee H., Lee J.K., Park M.H., Hong Y.R., Marti H.H., Kim H., Okada Y.,
RA Otsu M., Seo E.J., Park J.H., Bae J.H., Okino N., He X., Schuchman E.H.,
RA Bae J.S., Jin H.K.;
RT "Pathological roles of the VEGF/SphK pathway in Niemann-Pick type C
RT neurons.";
RL Nat. Commun. 5:5514-5514(2014).
RN [20]
RP FUNCTION.
RX PubMed=28049734; DOI=10.1074/jbc.m116.762377;
RA Lima S., Milstien S., Spiegel S.;
RT "Sphingosine and Sphingosine Kinase 1 Involvement in Endocytic Membrane
RT Trafficking.";
RL J. Biol. Chem. 292:3074-3088(2017).
RN [21]
RP TISSUE SPECIFICITY, SUBCELLULAR LOCATION, AND FUNCTION.
RX PubMed=29662056; DOI=10.1038/s41467-018-03674-2;
RA Lee J.Y., Han S.H., Park M.H., Baek B., Song I.S., Choi M.K., Takuwa Y.,
RA Ryu H., Kim S.H., He X., Schuchman E.H., Bae J.S., Jin H.K.;
RT "Neuronal SphK1 acetylates COX2 and contributes to pathogenesis in a model
RT of Alzheimer's Disease.";
RL Nat. Commun. 9:1479-1479(2018).
RN [22]
RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 9-364 IN COMPLEXES WITH SUBSTRATE
RP ANALOGS AND ADP, CATALYTIC ACTIVITY, FUNCTION, ACTIVE SITE, MUTAGENESIS OF
RP ASP-81, AND SUBSTRATE-BINDING REGION.
RX PubMed=23602659; DOI=10.1016/j.str.2013.02.025;
RA Wang Z., Min X., Xiao S.H., Johnstone S., Romanow W., Meininger D., Xu H.,
RA Liu J., Dai J., An S., Thibault S., Walker N.;
RT "Molecular basis of sphingosine kinase 1 substrate recognition and
RT catalysis.";
RL Structure 21:798-809(2013).
CC -!- FUNCTION: Catalyzes the phosphorylation of sphingosine to form
CC sphingosine 1-phosphate (SPP), a lipid mediator with both intra- and
CC extracellular functions. Also acts on D-erythro-sphingosine and to a
CC lesser extent sphinganine, but not other lipids, such as D,L-threo-
CC dihydrosphingosine, N,N-dimethylsphingosine, diacylglycerol, ceramide,
CC or phosphatidylinositol (PubMed:20577214, PubMed:23602659,
CC PubMed:29662056, PubMed:24929359, PubMed:11923095). In contrast to
CC proapoptotic SPHK2, has a negative effect on intracellular ceramide
CC levels, enhances cell growth and inhibits apoptosis (PubMed:16118219).
CC Involved in the regulation of inflammatory response and
CC neuroinflammation. Via the product sphingosine 1-phosphate, stimulates
CC TRAF2 E3 ubiquitin ligase activity, and promotes activation of NF-
CC kappa-B in response to TNF signaling leading to IL17 secretion
CC (PubMed:20577214). In response to TNF and in parallel to NF-kappa-B
CC activation, negatively regulates RANTES induction through p38 MAPK
CC signaling pathway (PubMed:23935096). Involved in endocytic membrane
CC trafficking induced by sphingosine, recruited to dilate endosomes, also
CC plays a role on later stages of endosomal maturation and membrane
CC fusion independently of its kinase activity (PubMed:28049734,
CC PubMed:24929359). In Purkinje cells, seems to be also involved in the
CC regulation of autophagosome-lysosome fusion upon VEGFA
CC (PubMed:25417698). {ECO:0000269|PubMed:11923095,
CC ECO:0000269|PubMed:16118219, ECO:0000269|PubMed:20577214,
CC ECO:0000269|PubMed:23602659, ECO:0000269|PubMed:23935096,
CC ECO:0000269|PubMed:24929359, ECO:0000269|PubMed:25417698,
CC ECO:0000269|PubMed:28049734, ECO:0000269|PubMed:29662056}.
CC -!- FUNCTION: Has serine acetyltransferase activity on PTGS2/COX2 in an
CC acetyl-CoA dependent manner. The acetyltransferase activity increases
CC in presence of the kinase substrate, sphingosine. During
CC neuroinflammation, through PTGS2 acetylation, promotes neuronal
CC secretion of specialized preresolving mediators (SPMs), especially 15-
CC R-lipoxin A4, which results in an increase of phagocytic microglia.
CC {ECO:0000250|UniProtKB:Q8CI15}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=a sphingoid base + ATP = a sphingoid 1-phosphate + ADP + H(+);
CC Xref=Rhea:RHEA:51496, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616,
CC ChEBI:CHEBI:76941, ChEBI:CHEBI:84410, ChEBI:CHEBI:456216;
CC EC=2.7.1.91; Evidence={ECO:0000269|PubMed:10802064,
CC ECO:0000269|PubMed:20577214, ECO:0000269|PubMed:23602659,
CC ECO:0000269|PubMed:24929359, ECO:0000269|PubMed:25417698};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:51497;
CC Evidence={ECO:0000269|PubMed:24929359, ECO:0000269|PubMed:25417698};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=acetyl-CoA + L-seryl-[protein] = CoA + O-acetyl-L-seryl-
CC [protein]; Xref=Rhea:RHEA:59392, Rhea:RHEA-COMP:9863, Rhea:RHEA-
CC COMP:15352, ChEBI:CHEBI:29999, ChEBI:CHEBI:57287, ChEBI:CHEBI:57288,
CC ChEBI:CHEBI:141128; Evidence={ECO:0000250|UniProtKB:Q8CI15};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:59393;
CC Evidence={ECO:0000250|UniProtKB:Q8CI15};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + sphinganine = ADP + H(+) + sphinganine 1-phosphate;
CC Xref=Rhea:RHEA:15465, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616,
CC ChEBI:CHEBI:57817, ChEBI:CHEBI:57939, ChEBI:CHEBI:456216;
CC EC=2.7.1.91; Evidence={ECO:0000269|PubMed:10802064,
CC ECO:0000269|PubMed:11923095};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:15466;
CC Evidence={ECO:0000269|PubMed:10802064, ECO:0000269|PubMed:11923095};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + sphing-4-enine = ADP + H(+) + sphing-4-enine 1-
CC phosphate; Xref=Rhea:RHEA:35847, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:30616, ChEBI:CHEBI:57756, ChEBI:CHEBI:60119,
CC ChEBI:CHEBI:456216; EC=2.7.1.91;
CC Evidence={ECO:0000269|PubMed:10802064, ECO:0000269|PubMed:11923095};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:35848;
CC Evidence={ECO:0000269|PubMed:10802064, ECO:0000269|PubMed:11923095};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=1-O-hexadecyl-2-amino-sn-glycerol + ATP = 1-O-hexadecyl-2-
CC desoxy-2-amino-sn-glycero-3-phosphate + ADP + H(+);
CC Xref=Rhea:RHEA:41163, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616,
CC ChEBI:CHEBI:77786, ChEBI:CHEBI:77787, ChEBI:CHEBI:456216;
CC Evidence={ECO:0000269|PubMed:11923095};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:41164;
CC Evidence={ECO:0000269|PubMed:11923095};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000269|PubMed:10947957};
CC -!- ACTIVITY REGULATION: Acetyltransferase activity increases in presence
CC of the kinase substrate, sphingosine (By similarity). In Purkinje
CC cells, kinase activity on sphingosine increases in presence of VEGFA
CC (PubMed:25417698). In neurons, kinase activity increases during the
CC first 24h in presence of Amyloid-beta protein 42 to decrease after 96h
CC (By similarity). {ECO:0000250|UniProtKB:Q8CI15,
CC ECO:0000250|UniProtKB:Q91V26, ECO:0000269|PubMed:25417698}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=14 uM for sphingosine {ECO:0000269|PubMed:10947957};
CC KM=20 uM for dihydrosphingosine {ECO:0000269|PubMed:10947957};
CC KM=77 uM for ATP {ECO:0000269|PubMed:10947957};
CC KM=3.8 uM for 1-O-hexadecyl-2-amino-sn-glycerol
CC {ECO:0000269|PubMed:11923095};
CC KM=15.7 uM for sphing-4-enine {ECO:0000269|PubMed:11923095};
CC KM=46 uM for sphinganine {ECO:0000269|PubMed:11923095};
CC KM=24 uM for sphingosine {ECO:0000269|PubMed:18263879};
CC KM=89 uM for ATP {ECO:0000269|PubMed:18263879};
CC Note=kcat is 124 sec(-1) for sphingosine and increases to 304 sec(-1)
CC upon interaction with EEF1A1. {ECO:0000269|PubMed:18263879};
CC pH dependence:
CC Optimum pH is 7.4. {ECO:0000269|PubMed:10947957};
CC -!- SUBUNIT: Interacts with ACY1 (By similarity). Binds to calmodulin.
CC Interacts with SPHKAP (PubMed:12080051). Interacts with CIB1, the
CC interaction occurs in a calcium-dependent manner (PubMed:19854831).
CC Interacts with TRAF2 (PubMed:20577214). Interacts with EEF1A1; the
CC interaction enhances SPHK1 kinase activity (PubMed:18263879).
CC {ECO:0000250|UniProtKB:Q8CI15, ECO:0000269|PubMed:12080051,
CC ECO:0000269|PubMed:18263879, ECO:0000269|PubMed:19854831,
CC ECO:0000269|PubMed:20577214}.
CC -!- INTERACTION:
CC Q9NYA1; P07858: CTSB; NbExp=4; IntAct=EBI-985303, EBI-715062;
CC Q9NYA1; P68104: EEF1A1; NbExp=2; IntAct=EBI-985303, EBI-352162;
CC Q9NYA1; Q14192: FHL2; NbExp=7; IntAct=EBI-985303, EBI-701903;
CC Q9NYA1; Q2M3C7: SPHKAP; NbExp=4; IntAct=EBI-985303, EBI-1803914;
CC Q9NYA1; Q9Y4K3: TRAF6; NbExp=2; IntAct=EBI-985303, EBI-359276;
CC Q9NYA1-2; P13473-2: LAMP2; NbExp=3; IntAct=EBI-12512419, EBI-21591415;
CC Q9NYA1-2; Q9Y371: SH3GLB1; NbExp=3; IntAct=EBI-12512419, EBI-2623095;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:14575709,
CC ECO:0000269|PubMed:19854831, ECO:0000269|PubMed:29662056}. Nucleus
CC {ECO:0000269|PubMed:14575709, ECO:0000269|PubMed:19854831,
CC ECO:0000269|PubMed:29662056}. Cell membrane
CC {ECO:0000269|PubMed:19854831}. Endosome membrane
CC {ECO:0000269|PubMed:24929359}; Peripheral membrane protein
CC {ECO:0000269|PubMed:24929359}. Membrane, clathrin-coated pit
CC {ECO:0000269|PubMed:24929359}. Synapse {ECO:0000250|UniProtKB:Q8CI15}.
CC Note=Translocated from the cytoplasm to the plasma membrane in a CIB1-
CC dependent manner (PubMed:19854831). Binds to membranes containing
CC negatively charged lipids but not neutral lipids (PubMed:24929359).
CC Recruited to endocytic membranes by sphingosine where promotes membrane
CC fusion (By similarity). {ECO:0000250|UniProtKB:Q8CI15,
CC ECO:0000269|PubMed:19854831, ECO:0000269|PubMed:24929359}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=Q9NYA1-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q9NYA1-2; Sequence=VSP_035453;
CC Name=3;
CC IsoId=Q9NYA1-3; Sequence=VSP_047078;
CC -!- TISSUE SPECIFICITY: Widely expressed with highest levels in adult
CC liver, kidney, heart and skeletal muscle. Expressed in brain cortex (at
CC protein level) (PubMed:29662056). {ECO:0000269|PubMed:10802064,
CC ECO:0000269|PubMed:29662056}.
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DR EMBL; AF266756; AAF73470.1; -; mRNA.
DR EMBL; AF238083; AAF73423.1; -; mRNA.
DR EMBL; AF200328; AAG01980.1; -; mRNA.
DR EMBL; AK023393; BAB14558.1; -; mRNA.
DR EMBL; AK292294; BAF84983.1; -; mRNA.
DR EMBL; AK022402; BAB14028.1; -; mRNA.
DR EMBL; AJ245504; CAB92131.1; -; mRNA.
DR EMBL; AC090699; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471099; EAW89392.1; -; Genomic_DNA.
DR EMBL; CH471099; EAW89393.1; -; Genomic_DNA.
DR EMBL; BC009419; AAH09419.1; -; mRNA.
DR EMBL; BC014439; AAH14439.1; -; mRNA.
DR EMBL; BC030553; AAH30553.1; -; mRNA.
DR CCDS; CCDS11744.1; -. [Q9NYA1-2]
DR CCDS; CCDS45785.1; -. [Q9NYA1-1]
DR CCDS; CCDS59297.1; -. [Q9NYA1-3]
DR RefSeq; NP_001136073.1; NM_001142601.1. [Q9NYA1-1]
DR RefSeq; NP_001136074.1; NM_001142602.1. [Q9NYA1-1]
DR RefSeq; NP_068807.2; NM_021972.3. [Q9NYA1-3]
DR RefSeq; NP_892010.2; NM_182965.2. [Q9NYA1-2]
DR RefSeq; XP_005257823.1; XM_005257766.2.
DR PDB; 3VZB; X-ray; 2.00 A; A/B/C=9-364.
DR PDB; 3VZC; X-ray; 2.30 A; A/B/C/D/E/F=9-364.
DR PDB; 3VZD; X-ray; 2.30 A; A/B/C/D/E/F=9-364.
DR PDB; 4L02; X-ray; 2.75 A; A/B/C=9-364.
DR PDB; 4V24; X-ray; 1.80 A; A/B=1-363.
DR PDBsum; 3VZB; -.
DR PDBsum; 3VZC; -.
DR PDBsum; 3VZD; -.
DR PDBsum; 4L02; -.
DR PDBsum; 4V24; -.
DR AlphaFoldDB; Q9NYA1; -.
DR SMR; Q9NYA1; -.
DR BioGRID; 114396; 51.
DR IntAct; Q9NYA1; 60.
DR MINT; Q9NYA1; -.
DR STRING; 9606.ENSP00000313681; -.
DR BindingDB; Q9NYA1; -.
DR ChEMBL; CHEMBL4394; -.
DR DrugBank; DB08868; Fingolimod.
DR GuidetoPHARMACOLOGY; 2204; -.
DR SwissLipids; SLP:000000111; -.
DR iPTMnet; Q9NYA1; -.
DR PhosphoSitePlus; Q9NYA1; -.
DR BioMuta; SPHK1; -.
DR DMDM; 17369329; -.
DR EPD; Q9NYA1; -.
DR jPOST; Q9NYA1; -.
DR MassIVE; Q9NYA1; -.
DR MaxQB; Q9NYA1; -.
DR PaxDb; Q9NYA1; -.
DR PeptideAtlas; Q9NYA1; -.
DR PRIDE; Q9NYA1; -.
DR ProteomicsDB; 83202; -. [Q9NYA1-1]
DR ProteomicsDB; 83203; -. [Q9NYA1-2]
DR Antibodypedia; 19687; 754 antibodies from 48 providers.
DR DNASU; 8877; -.
DR Ensembl; ENST00000323374.8; ENSP00000313681.3; ENSG00000176170.14. [Q9NYA1-2]
DR Ensembl; ENST00000392496.3; ENSP00000376285.2; ENSG00000176170.14. [Q9NYA1-1]
DR Ensembl; ENST00000545180.5; ENSP00000440970.1; ENSG00000176170.14. [Q9NYA1-1]
DR Ensembl; ENST00000590959.5; ENSP00000468547.1; ENSG00000176170.14. [Q9NYA1-3]
DR Ensembl; ENST00000592299.6; ENSP00000465726.2; ENSG00000176170.14. [Q9NYA1-1]
DR GeneID; 8877; -.
DR KEGG; hsa:8877; -.
DR MANE-Select; ENST00000592299.6; ENSP00000465726.2; NM_001142601.2; NP_001136073.1.
DR UCSC; uc002jrf.1; human. [Q9NYA1-1]
DR CTD; 8877; -.
DR DisGeNET; 8877; -.
DR GeneCards; SPHK1; -.
DR HGNC; HGNC:11240; SPHK1.
DR HPA; ENSG00000176170; Low tissue specificity.
DR MIM; 603730; gene.
DR neXtProt; NX_Q9NYA1; -.
DR OpenTargets; ENSG00000176170; -.
DR PharmGKB; PA36070; -.
DR VEuPathDB; HostDB:ENSG00000176170; -.
DR eggNOG; KOG1116; Eukaryota.
DR GeneTree; ENSGT00940000157864; -.
DR HOGENOM; CLU_013399_1_0_1; -.
DR InParanoid; Q9NYA1; -.
DR OMA; AECDLGT; -.
DR OrthoDB; 681139at2759; -.
DR PhylomeDB; Q9NYA1; -.
DR TreeFam; TF354296; -.
DR BRENDA; 2.7.1.91; 2681.
DR PathwayCommons; Q9NYA1; -.
DR Reactome; R-HSA-1660661; Sphingolipid de novo biosynthesis.
DR Reactome; R-HSA-390471; Association of TriC/CCT with target proteins during biosynthesis.
DR Reactome; R-HSA-5218921; VEGFR2 mediated cell proliferation.
DR Reactome; R-HSA-9009391; Extra-nuclear estrogen signaling.
DR SABIO-RK; Q9NYA1; -.
DR SignaLink; Q9NYA1; -.
DR SIGNOR; Q9NYA1; -.
DR BioGRID-ORCS; 8877; 15 hits in 1083 CRISPR screens.
DR ChiTaRS; SPHK1; human.
DR GeneWiki; Sphingosine_kinase_1; -.
DR GenomeRNAi; 8877; -.
DR Pharos; Q9NYA1; Tchem.
DR PRO; PR:Q9NYA1; -.
DR Proteomes; UP000005640; Chromosome 17.
DR RNAct; Q9NYA1; protein.
DR Bgee; ENSG00000176170; Expressed in stromal cell of endometrium and 132 other tissues.
DR ExpressionAtlas; Q9NYA1; baseline and differential.
DR Genevisible; Q9NYA1; HS.
DR GO; GO:0070161; C:anchoring junction; IEA:UniProtKB-KW.
DR GO; GO:0005905; C:clathrin-coated pit; IDA:UniProtKB.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; IDA:HPA.
DR GO; GO:0031901; C:early endosome membrane; IDA:UniProtKB.
DR GO; GO:0030139; C:endocytic vesicle; ISS:UniProtKB.
DR GO; GO:0043231; C:intracellular membrane-bounded organelle; IBA:GO_Central.
DR GO; GO:0016020; C:membrane; IBA:GO_Central.
DR GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR GO; GO:0098793; C:presynapse; ISS:UniProtKB.
DR GO; GO:0016407; F:acetyltransferase activity; ISS:UniProtKB.
DR GO; GO:0005524; F:ATP binding; IDA:UniProtKB.
DR GO; GO:0005516; F:calmodulin binding; IDA:UniProtKB.
DR GO; GO:0017050; F:D-erythro-sphingosine kinase activity; IDA:UniProtKB.
DR GO; GO:0003677; F:DNA binding; IDA:MGI.
DR GO; GO:0008289; F:lipid binding; IDA:UniProtKB.
DR GO; GO:0001727; F:lipid kinase activity; IBA:GO_Central.
DR GO; GO:0000287; F:magnesium ion binding; IDA:UniProtKB.
DR GO; GO:0003951; F:NAD+ kinase activity; IEA:InterPro.
DR GO; GO:0051721; F:protein phosphatase 2A binding; IPI:BHF-UCL.
DR GO; GO:0008481; F:sphinganine kinase activity; IDA:UniProtKB.
DR GO; GO:0038036; F:sphingosine-1-phosphate receptor activity; IMP:UniProtKB.
DR GO; GO:0001568; P:blood vessel development; IEA:Ensembl.
DR GO; GO:0007420; P:brain development; IEA:Ensembl.
DR GO; GO:0019722; P:calcium-mediated signaling; IDA:UniProtKB.
DR GO; GO:0008283; P:cell population proliferation; IEA:Ensembl.
DR GO; GO:0071363; P:cellular response to growth factor stimulus; IBA:GO_Central.
DR GO; GO:0070301; P:cellular response to hydrogen peroxide; IEA:Ensembl.
DR GO; GO:0035924; P:cellular response to vascular endothelial growth factor stimulus; IDA:UniProtKB.
DR GO; GO:0071897; P:DNA biosynthetic process; IEA:Ensembl.
DR GO; GO:0006954; P:inflammatory response; IEA:Ensembl.
DR GO; GO:0035556; P:intracellular signal transduction; TAS:UniProtKB.
DR GO; GO:0043066; P:negative regulation of apoptotic process; IDA:MGI.
DR GO; GO:1900060; P:negative regulation of ceramide biosynthetic process; IDA:UniProtKB.
DR GO; GO:0016310; P:phosphorylation; IBA:GO_Central.
DR GO; GO:0045766; P:positive regulation of angiogenesis; IDA:UniProtKB.
DR GO; GO:0030307; P:positive regulation of cell growth; IDA:UniProtKB.
DR GO; GO:0030335; P:positive regulation of cell migration; IDA:UniProtKB.
DR GO; GO:0048146; P:positive regulation of fibroblast proliferation; IDA:MGI.
DR GO; GO:0032740; P:positive regulation of interleukin-17 production; ISS:UniProtKB.
DR GO; GO:0045931; P:positive regulation of mitotic cell cycle; IDA:UniProtKB.
DR GO; GO:0045840; P:positive regulation of mitotic nuclear division; IEA:Ensembl.
DR GO; GO:0051092; P:positive regulation of NF-kappaB transcription factor activity; IMP:UniProtKB.
DR GO; GO:1901224; P:positive regulation of NIK/NF-kappaB signaling; IMP:UniProtKB.
DR GO; GO:1900745; P:positive regulation of p38MAPK cascade; IDA:UniProtKB.
DR GO; GO:0010800; P:positive regulation of peptidyl-threonine phosphorylation; IMP:UniProtKB.
DR GO; GO:0031398; P:positive regulation of protein ubiquitination; IDA:UniProtKB.
DR GO; GO:0045987; P:positive regulation of smooth muscle contraction; IDA:UniProtKB.
DR GO; GO:0006473; P:protein acetylation; ISS:UniProtKB.
DR GO; GO:0030100; P:regulation of endocytosis; IDA:UniProtKB.
DR GO; GO:1905364; P:regulation of endosomal vesicle fusion; ISS:UniProtKB.
DR GO; GO:0032651; P:regulation of interleukin-1 beta production; IEA:Ensembl.
DR GO; GO:1903978; P:regulation of microglial cell activation; ISS:UniProtKB.
DR GO; GO:0150077; P:regulation of neuroinflammatory response; ISS:UniProtKB.
DR GO; GO:0050764; P:regulation of phagocytosis; ISS:UniProtKB.
DR GO; GO:0010803; P:regulation of tumor necrosis factor-mediated signaling pathway; IDA:UniProtKB.
DR GO; GO:0034612; P:response to tumor necrosis factor; IDA:UniProtKB.
DR GO; GO:0046521; P:sphingoid catabolic process; NAS:UniProtKB.
DR GO; GO:0030148; P:sphingolipid biosynthetic process; TAS:Reactome.
DR GO; GO:0006665; P:sphingolipid metabolic process; IBA:GO_Central.
DR GO; GO:0046512; P:sphingosine biosynthetic process; IMP:UniProtKB.
DR GO; GO:0006670; P:sphingosine metabolic process; IDA:UniProtKB.
DR Gene3D; 3.40.50.10330; -; 1.
DR InterPro; IPR017438; ATP-NAD_kinase_N.
DR InterPro; IPR001206; Diacylglycerol_kinase_cat_dom.
DR InterPro; IPR016064; NAD/diacylglycerol_kinase_sf.
DR Pfam; PF00781; DAGK_cat; 1.
DR SMART; SM00046; DAGKc; 1.
DR SUPFAM; SSF111331; SSF111331; 1.
DR PROSITE; PS50146; DAGK; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; ATP-binding; Calmodulin-binding;
KW Cell membrane; Coated pit; Cytoplasm; Endosome; Kinase; Lipid metabolism;
KW Membrane; Nucleotide-binding; Nucleus; Phosphoprotein; Reference proteome;
KW Synapse; Transferase.
FT CHAIN 1..384
FT /note="Sphingosine kinase 1"
FT /id="PRO_0000181357"
FT DOMAIN 12..159
FT /note="DAGKc"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00783"
FT MOTIF 147..155
FT /note="Nuclear export signal 1"
FT /evidence="ECO:0000269|PubMed:14575709"
FT MOTIF 161..169
FT /note="Nuclear export signal 2"
FT /evidence="ECO:0000269|PubMed:14575709"
FT ACT_SITE 81
FT /note="Proton donor/acceptor"
FT /evidence="ECO:0000269|PubMed:23602659"
FT BINDING 22..24
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000269|PubMed:23602659"
FT BINDING 54..58
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000269|PubMed:23602659"
FT BINDING 79..82
FT /ligand="substrate"
FT /evidence="ECO:0000269|PubMed:23602659"
FT BINDING 86
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000269|PubMed:23602659"
FT BINDING 111..113
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000269|PubMed:23602659"
FT BINDING 178
FT /ligand="substrate"
FT /evidence="ECO:0000269|PubMed:23602659"
FT BINDING 185
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000269|PubMed:23602659"
FT BINDING 191
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000269|PubMed:23602659"
FT BINDING 341..343
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000269|PubMed:23602659"
FT MOD_RES 193
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:18669648"
FT MOD_RES 225
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:20577214"
FT VAR_SEQ 1
FT /note="M -> MSAQVLGFLRSWTPLPLAAPRGPAAAGNDAGAPAATAPGGEGEPHSR
FT PCDARLGSTDKELKAGAAATGSAPTAPGTPWQREPRVEVM (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:14702039,
FT ECO:0000303|PubMed:15489334"
FT /id="VSP_035453"
FT VAR_SEQ 3
FT /note="P -> PVVGCGRGLFGFVFS (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_047078"
FT MUTAGEN 81
FT /note="D->A: Loss of enzyme activity."
FT /evidence="ECO:0000269|PubMed:23602659"
FT MUTAGEN 81
FT /note="D->N: Strongly reduced enzyme activity."
FT /evidence="ECO:0000269|PubMed:23602659"
FT MUTAGEN 82
FT /note="G->D: Loss of enzyme activity."
FT /evidence="ECO:0000269|PubMed:20577214"
FT MUTAGEN 194
FT /note="L->Q: Loss of binding to negatively charged
FT membranes, diffuse cytosolic distribution."
FT /evidence="ECO:0000269|PubMed:24929359"
FT MUTAGEN 197..198
FT /note="FL->AA: Abolishes interaction with CIB1."
FT /evidence="ECO:0000269|PubMed:19854831"
FT MUTAGEN 197..198
FT /note="FL->AQ: Loss of binding to negatively charged
FT membranes, diffuse cytosolic distribution."
FT /evidence="ECO:0000269|PubMed:24929359"
FT CONFLICT 6
FT /note="Missing (in Ref. 4; CAB92131)"
FT /evidence="ECO:0000305"
FT CONFLICT 11..15
FT /note="LPRPC -> ARL (in Ref. 4; CAB92131)"
FT /evidence="ECO:0000305"
FT CONFLICT 114..115
FT /note="NA -> KP (in Ref. 4; CAB92131)"
FT /evidence="ECO:0000305"
FT CONFLICT 251
FT /note="V -> M (in Ref. 2; AAF73423)"
FT /evidence="ECO:0000305"
FT CONFLICT 260
FT /note="V -> I (in Ref. 2; AAF73423)"
FT /evidence="ECO:0000305"
FT CONFLICT 302
FT /note="L -> F (in Ref. 2; AAF73423)"
FT /evidence="ECO:0000305"
FT CONFLICT 325
FT /note="V -> G (in Ref. 4; CAB92131)"
FT /evidence="ECO:0000305"
FT CONFLICT 337
FT /note="V -> M (in Ref. 3; AAG01980)"
FT /evidence="ECO:0000305"
FT STRAND 13..21
FT /evidence="ECO:0007829|PDB:4V24"
FT TURN 26..29
FT /evidence="ECO:0007829|PDB:4V24"
FT HELIX 30..37
FT /evidence="ECO:0007829|PDB:4V24"
FT HELIX 39..44
FT /evidence="ECO:0007829|PDB:4V24"
FT STRAND 47..53
FT /evidence="ECO:0007829|PDB:4V24"
FT HELIX 59..66
FT /evidence="ECO:0007829|PDB:4V24"
FT HELIX 69..71
FT /evidence="ECO:0007829|PDB:3VZB"
FT STRAND 73..80
FT /evidence="ECO:0007829|PDB:4V24"
FT HELIX 81..92
FT /evidence="ECO:0007829|PDB:4V24"
FT HELIX 97..100
FT /evidence="ECO:0007829|PDB:4V24"
FT STRAND 105..109
FT /evidence="ECO:0007829|PDB:4V24"
FT HELIX 115..123
FT /evidence="ECO:0007829|PDB:4V24"
FT HELIX 131..144
FT /evidence="ECO:0007829|PDB:4V24"
FT STRAND 146..157
FT /evidence="ECO:0007829|PDB:4V24"
FT STRAND 162..172
FT /evidence="ECO:0007829|PDB:4V24"
FT HELIX 173..181
FT /evidence="ECO:0007829|PDB:4V24"
FT HELIX 182..190
FT /evidence="ECO:0007829|PDB:4V24"
FT HELIX 191..201
FT /evidence="ECO:0007829|PDB:4V24"
FT STRAND 206..214
FT /evidence="ECO:0007829|PDB:4V24"
FT HELIX 215..218
FT /evidence="ECO:0007829|PDB:4V24"
FT STRAND 230..232
FT /evidence="ECO:0007829|PDB:3VZB"
FT STRAND 249..251
FT /evidence="ECO:0007829|PDB:4V24"
FT STRAND 255..266
FT /evidence="ECO:0007829|PDB:4V24"
FT STRAND 285..291
FT /evidence="ECO:0007829|PDB:4V24"
FT HELIX 296..305
FT /evidence="ECO:0007829|PDB:4V24"
FT HELIX 306..308
FT /evidence="ECO:0007829|PDB:4V24"
FT HELIX 311..314
FT /evidence="ECO:0007829|PDB:4V24"
FT STRAND 319..331
FT /evidence="ECO:0007829|PDB:4V24"
FT STRAND 333..335
FT /evidence="ECO:0007829|PDB:4V24"
FT STRAND 337..340
FT /evidence="ECO:0007829|PDB:4V24"
FT STRAND 343..346
FT /evidence="ECO:0007829|PDB:4V24"
FT STRAND 350..362
FT /evidence="ECO:0007829|PDB:4V24"
FT VARIANT Q9NYA1-2:34
FT /note="A -> T (in dbSNP:rs346803)"
FT /evidence="ECO:0000305"
FT /id="VAR_082919"
SQ SEQUENCE 384 AA; 42518 MW; EB04A7F2034C2DB0 CRC64;
MDPAGGPRGV LPRPCRVLVL LNPRGGKGKA LQLFRSHVQP LLAEAEISFT LMLTERRNHA
RELVRSEELG RWDALVVMSG DGLMHEVVNG LMERPDWETA IQKPLCSLPA GSGNALAASL
NHYAGYEQVT NEDLLTNCTL LLCRRLLSPM NLLSLHTASG LRLFSVLSLA WGFIADVDLE
SEKYRRLGEM RFTLGTFLRL AALRTYRGRL AYLPVGRVGS KTPASPVVVQ QGPVDAHLVP
LEEPVPSHWT VVPDEDFVLV LALLHSHLGS EMFAAPMGRC AAGVMHLFYV RAGVSRAMLL
RLFLAMEKGR HMEYECPYLV YVPVVAFRLE PKDGKGVFAV DGELMVSEAV QGQVHPNYFW
MVSGCVEPPP SWKPQQMPPP EEPL
