S19A1_HUMAN
ID S19A1_HUMAN Reviewed; 591 AA.
AC P41440; B2R7U8; B7Z8C3; E9PFY4; O00553; O60227; Q13026; Q9BTX8;
DT 01-NOV-1995, integrated into UniProtKB/Swiss-Prot.
DT 01-DEC-2000, sequence version 3.
DT 03-AUG-2022, entry version 183.
DE RecName: Full=Reduced folate transporter {ECO:0000305};
DE Short=FOLT {ECO:0000303|PubMed:7826387};
DE AltName: Full=Cyclic dinucleotide:anion antiporter SLC19A1 {ECO:0000305|PubMed:31126740, ECO:0000305|PubMed:31511694};
DE AltName: Full=Folate:anion antiporter SLC19A1 {ECO:0000305|PubMed:10787414, ECO:0000305|PubMed:14609557, ECO:0000305|PubMed:22554803};
DE AltName: Full=Intestinal folate carrier 1 {ECO:0000303|PubMed:9041240};
DE Short=IFC-1 {ECO:0000303|PubMed:9041240};
DE AltName: Full=Placental folate transporter {ECO:0000303|PubMed:7826387};
DE AltName: Full=Reduced folate carrier protein {ECO:0000303|PubMed:7615551};
DE Short=RFC {ECO:0000303|PubMed:22554803, ECO:0000303|PubMed:7615551};
DE Short=hRFC {ECO:0000303|PubMed:16115875};
DE AltName: Full=Reduced folate transporter 1 {ECO:0000303|PubMed:10787414};
DE Short=RFT-1 {ECO:0000303|PubMed:10787414};
DE AltName: Full=Solute carrier family 19 member 1 {ECO:0000305};
DE Short=hSLC19A1 {ECO:0000303|PubMed:31511694};
GN Name=SLC19A1 {ECO:0000312|HGNC:HGNC:10937};
GN Synonyms=FLOT1, RFC1 {ECO:0000303|PubMed:7615551};
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), FUNCTION, TISSUE SPECIFICITY, AND
RP VARIANT ARG-27.
RC TISSUE=Placenta;
RX PubMed=7826387; DOI=10.1006/bbrc.1995.1096;
RA Prasad P.D., Ramamoorthy S., Leibach F.H., Ganapathy V.;
RT "Molecular cloning of the human placental folate transporter.";
RL Biochem. Biophys. Res. Commun. 206:681-687(1995).
RN [2]
RP SEQUENCE REVISION TO 490-527.
RA Prasad P.D.;
RL Submitted (APR-1996) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, AND VARIANT ARG-27.
RX PubMed=7615551; DOI=10.1074/jbc.270.29.17468;
RA Wong S.C., Proefke A., Bhushan A., Matherly L.H.;
RT "Isolation of human cDNAs that restore methotrexate sensitivity and reduced
RT folate carrier activity in methotrexate transport-defective Chinese hamster
RT ovary cells.";
RL J. Biol. Chem. 270:17468-17475(1995).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, AND VARIANT ARG-27.
RC TISSUE=Testis;
RX PubMed=7641195;
RA Moscow J.A., Gong M., He R., Sgagias M.K., Dixon K.H., Anzick S.L.,
RA Meltzer P.S., Cowan K.H.;
RT "Isolation of a gene encoding a human reduced folate carrier (RFC1) and
RT analysis of its expression in transport-deficient, methotrexate-resistant
RT human breast cancer cells.";
RL Cancer Res. 55:3790-3794(1995).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Lymphoma;
RX PubMed=7852378; DOI=10.1074/jbc.270.7.2987;
RA Williams F.M., Flintoff W.F.;
RT "Isolation of a human cDNA that complements a mutant hamster cell defective
RT in methotrexate uptake.";
RL J. Biol. Chem. 270:2987-2992(1995).
RN [6]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT ARG-27.
RC TISSUE=Liver;
RX PubMed=9602167; DOI=10.1016/s0378-1119(98)00123-1;
RA Tolner B., Roy K., Sirotnak F.M.;
RT "Structural analysis of the human RFC-1 gene encoding a folate transporter
RT reveals multiple promoters and alternatively spliced transcripts with 5'
RT end heterogeneity.";
RL Gene 211:331-341(1998).
RN [7]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND FUNCTION.
RC TISSUE=Small intestine;
RX PubMed=9041240; DOI=10.1053/gast.1997.v112.pm9041240;
RA Nguyen T.T., Dyer D.L., Dunning D.D., Rubin S.A., Grant K.E., Said H.M.;
RT "Human intestinal folate transport: cloning, expression, and distribution
RT of complementary RNA.";
RL Gastroenterology 112:783-791(1997).
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Thymus, and Tongue;
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 [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=10830953; DOI=10.1038/35012518;
RA Hattori M., Fujiyama A., Taylor T.D., Watanabe H., Yada T., Park H.-S.,
RA Toyoda A., Ishii K., Totoki Y., Choi D.-K., Groner Y., Soeda E., Ohki M.,
RA Takagi T., Sakaki Y., Taudien S., Blechschmidt K., Polley A., Menzel U.,
RA Delabar J., Kumpf K., Lehmann R., Patterson D., Reichwald K., Rump A.,
RA Schillhabel M., Schudy A., Zimmermann W., Rosenthal A., Kudoh J.,
RA Shibuya K., Kawasaki K., Asakawa S., Shintani A., Sasaki T., Nagamine K.,
RA Mitsuyama S., Antonarakis S.E., Minoshima S., Shimizu N., Nordsiek G.,
RA Hornischer K., Brandt P., Scharfe M., Schoen O., Desario A., Reichelt J.,
RA Kauer G., Bloecker H., Ramser J., Beck A., Klages S., Hennig S.,
RA Riesselmann L., Dagand E., Wehrmeyer S., Borzym K., Gardiner K.,
RA Nizetic D., Francis F., Lehrach H., Reinhardt R., Yaspo M.-L.;
RT "The DNA sequence of human chromosome 21.";
RL Nature 405:311-319(2000).
RN [10]
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 (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [11]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3), AND VARIANT ARG-27.
RC TISSUE=Brain;
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 [12]
RP FUNCTION, GLYCOSYLATION AT ASN-58, AND MUTAGENESIS OF ASN-58.
RX PubMed=9767079; DOI=10.1016/s0005-2736(98)00118-7;
RA Wong S.C., Zhang L., Proefke S.A., Matherly L.H.;
RT "Effects of the loss of capacity for N-glycosylation on the transport
RT activity and cellular localization of the human reduced folate carrier.";
RL Biochim. Biophys. Acta 1375:6-12(1998).
RN [13]
RP SUBCELLULAR LOCATION, AND TOPOLOGY.
RX PubMed=10347183; DOI=10.1074/jbc.274.23.16269;
RA Ferguson P.L., Flintoff W.F.;
RT "Topological and functional analysis of the human reduced folate carrier by
RT hemagglutinin epitope insertion.";
RL J. Biol. Chem. 274:16269-16278(1999).
RN [14]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=10787414; DOI=10.1074/jbc.m002328200;
RA Chancy C.D., Kekuda R., Huang W., Prasad P.D., Kuhnel J.M., Sirotnak F.M.,
RA Roon P., Ganapathy V., Smith S.B.;
RT "Expression and differential polarization of the reduced-folate
RT transporter-1 and the folate receptor alpha in mammalian retinal pigment
RT epithelium.";
RL J. Biol. Chem. 275:20676-20684(2000).
RN [15]
RP FUNCTION, AND TRANSPORTER ACTIVITY.
RX PubMed=14609557; DOI=10.1016/j.exer.2003.08.013;
RA Naggar H., Fei Y.J., Ganapathy V., Smith S.B.;
RT "Regulation of reduced-folate transporter-1 (RFT-1) by homocysteine and
RT identity of transport systems for homocysteine uptake in retinal pigment
RT epithelial (RPE) cells.";
RL Exp. Eye Res. 77:687-697(2003).
RN [16]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=15337749; DOI=10.1074/jbc.m408696200;
RA Witt T.L., Stapels S.E., Matherly L.H.;
RT "Restoration of transport activity by co-expression of human reduced folate
RT carrier half-molecules in transport-impaired K562 cells: localization of a
RT substrate binding domain to transmembrane domains 7-12.";
RL J. Biol. Chem. 279:46755-46763(2004).
RN [17]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=16115875; DOI=10.1074/jbc.m507295200;
RA Hou Z., Stapels S.E., Haska C.L., Matherly L.H.;
RT "Localization of a substrate binding domain of the human reduced folate
RT carrier to transmembrane domain 11 by radioaffinity labeling and cysteine-
RT substituted accessibility methods.";
RL J. Biol. Chem. 280:36206-36213(2005).
RN [18]
RP IDENTIFICATION BY 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 [19]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in a
RT refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [20]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-499 AND SER-503, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full phosphorylation
RT site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [21]
RP FUNCTION, AND TRANSPORTER ACTIVITY.
RX PubMed=22554803; DOI=10.1124/mol.112.078642;
RA Visentin M., Zhao R., Goldman I.D.;
RT "Augmentation of reduced folate carrier-mediated folate/antifolate
RT transport through an antiport mechanism with 5-aminoimidazole-4-carboxamide
RT riboside monophosphate.";
RL Mol. Pharmacol. 82:209-216(2012).
RN [22]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND IDENTIFICATION BY MASS
RP SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E., Timmerman E.,
RA Prieto J., Arnesen T., Sherman F., Gevaert K., Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-terminal
RT acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [23]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-5 AND SER-225, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma, and 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 [24]
RP FUNCTION, AND TRANSPORTER ACTIVITY.
RX PubMed=31511694; DOI=10.1038/s41586-019-1553-0;
RA Luteijn R.D., Zaver S.A., Gowen B.G., Wyman S.K., Garelis N.E., Onia L.,
RA McWhirter S.M., Katibah G.E., Corn J.E., Woodward J.J., Raulet D.H.;
RT "SLC19A1 transports immunoreactive cyclic dinucleotides.";
RL Nature 573:434-438(2019).
RN [25]
RP FUNCTION, AND TRANSPORTER ACTIVITY.
RX PubMed=31126740; DOI=10.1016/j.molcel.2019.05.006;
RA Ritchie C., Cordova A.F., Hess G.T., Bassik M.C., Li L.;
RT "SLC19A1 is an importer of the immunotransmitter cGAMP.";
RL Mol. Cell 0:0-0(2019).
RN [26]
RP INVOLVEMENT IN MEGAF, VARIANT MEGAF PHE-212 DEL, CHARACTERIZATION OF
RP VARIANT MEGAF PHE-212 DEL, AND FUNCTION.
RX PubMed=32276275; DOI=10.1182/blood.2019003178;
RA Svaton M., Skvarova Kramarzova K., Kanderova V., Mancikova A., Smisek P.,
RA Jesina P., Krijt J., Stiburkova B., Dobrovolny R., Sokolova J.,
RA Bakardjieva-Mihaylova V., Vodickova E., Rackova M., Stuchly J., Kalina T.,
RA Stary J., Trka J., Fronkova E., Kozich V.;
RT "A homozygous deletion in the SLC19A1 gene as a cause of folate-dependent
RT recurrent megaloblastic anemia.";
RL Blood 135:2427-2431(2020).
CC -!- FUNCTION: Antiporter that mediates the import of reduced folates or a
CC subset of cyclic dinucleotides, driven by the export of organic anions
CC (PubMed:7826387, PubMed:9041240, PubMed:10787414, PubMed:15337749,
CC PubMed:16115875, PubMed:22554803, PubMed:31511694, PubMed:31126740,
CC PubMed:32276275). Mechanistically, acts as a secondary active
CC transporter, which exports intracellular organic anions down their
CC concentration gradients to facilitate the uptake of its substrates
CC (PubMed:22554803, PubMed:31511694, PubMed:31126740). Has high affinity
CC for N5-methyltetrahydrofolate, the predominant circulating form of
CC folate (PubMed:10787414, PubMed:14609557, PubMed:22554803). Also able
CC to mediate the import of antifolate drug methotrexate (PubMed:7615551,
CC PubMed:7641195, PubMed:9767079, PubMed:22554803). Also acts as an
CC importer of immunoreactive cyclic dinucleotides, such as cyclic GMP-AMP
CC (2'-3'-cGAMP), an immune messenger produced in response to DNA virus in
CC the cytosol, and its linkage isomer 3'-3'-cGAMP, thus playing a role in
CC triggering larger immune responses (PubMed:31511694, PubMed:31126740).
CC 5-amino-4-imidazolecarboxamide riboside (AICAR), when phosphorylated to
CC AICAR monophosphate, can serve as an organic anion for antiporter
CC activity (PubMed:22554803). {ECO:0000269|PubMed:10787414,
CC ECO:0000269|PubMed:14609557, ECO:0000269|PubMed:15337749,
CC ECO:0000269|PubMed:16115875, ECO:0000269|PubMed:22554803,
CC ECO:0000269|PubMed:31126740, ECO:0000269|PubMed:31511694,
CC ECO:0000269|PubMed:32276275, ECO:0000269|PubMed:7615551,
CC ECO:0000269|PubMed:7641195, ECO:0000269|PubMed:7826387,
CC ECO:0000269|PubMed:9041240, ECO:0000269|PubMed:9767079}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(6S)-5-methyl-5,6,7,8-tetrahydrofolate(out) + 5-amino-1-(5-
CC phospho-beta-D-ribosyl)imidazole-4-carboxamide(in) = (6S)-5-methyl-
CC 5,6,7,8-tetrahydrofolate(in) + 5-amino-1-(5-phospho-beta-D-
CC ribosyl)imidazole-4-carboxamide(out); Xref=Rhea:RHEA:60460,
CC ChEBI:CHEBI:18608, ChEBI:CHEBI:58475;
CC Evidence={ECO:0000269|PubMed:14609557, ECO:0000269|PubMed:22554803};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:60461;
CC Evidence={ECO:0000269|PubMed:14609557, ECO:0000269|PubMed:22554803};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=2',3'-cGAMP(out) + 5-amino-1-(5-phospho-beta-D-
CC ribosyl)imidazole-4-carboxamide(in) = 2',3'-cGAMP(in) + 5-amino-1-(5-
CC phospho-beta-D-ribosyl)imidazole-4-carboxamide(out);
CC Xref=Rhea:RHEA:60464, ChEBI:CHEBI:58475, ChEBI:CHEBI:143093;
CC Evidence={ECO:0000269|PubMed:31126740, ECO:0000305|PubMed:31511694};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:60465;
CC Evidence={ECO:0000269|PubMed:31126740, ECO:0000305|PubMed:31511694};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=3',3'-cGAMP(out) + 5-amino-1-(5-phospho-beta-D-
CC ribosyl)imidazole-4-carboxamide(in) = 3',3'-cGAMP(in) + 5-amino-1-(5-
CC phospho-beta-D-ribosyl)imidazole-4-carboxamide(out);
CC Xref=Rhea:RHEA:60468, ChEBI:CHEBI:58475, ChEBI:CHEBI:71501;
CC Evidence={ECO:0000269|PubMed:31126740};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:60469;
CC Evidence={ECO:0000269|PubMed:31126740};
CC -!- INTERACTION:
CC P41440-3; Q7Z3Y9: KRT26; NbExp=3; IntAct=EBI-17438674, EBI-12084444;
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:10347183,
CC ECO:0000269|PubMed:10787414, ECO:0000269|PubMed:15337749,
CC ECO:0000269|PubMed:16115875, ECO:0000269|PubMed:9767079}; Multi-pass
CC membrane protein {ECO:0000255}. Apical cell membrane
CC {ECO:0000269|PubMed:10787414}; Multi-pass membrane protein
CC {ECO:0000255}. Basolateral cell membrane {ECO:0000269|PubMed:10787414};
CC Multi-pass membrane protein {ECO:0000255}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=P41440-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P41440-2; Sequence=VSP_042891;
CC Name=3;
CC IsoId=P41440-3; Sequence=VSP_044497;
CC -!- TISSUE SPECIFICITY: Placenta, liver, and to a much smaller extent, in
CC lung. {ECO:0000269|PubMed:7826387}.
CC -!- DISEASE: Megaloblastic anemia, folate-responsive (MEGAF) [MIM:601775]:
CC An autosomal recessive metabolic disorder characterized by
CC megaloblastic anemia resulting from decreased folate transport into
CC erythrocytes. Disease manifestations include hemolytic anemia,
CC hyperhomocysteinemia, and low vitamin B12. Serum folate levels are
CC normal, but erythrocyte folate levels are decreased. Treatment with
CC oral folate corrects the anemia and normalizes homocysteine.
CC {ECO:0000269|PubMed:32276275}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the reduced folate carrier (RFC) transporter (TC
CC 2.A.48) family. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=CAB90483.1; Type=Erroneous gene model prediction; Evidence={ECO:0000305};
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DR EMBL; U15939; AAA98442.1; -; mRNA.
DR EMBL; U19720; AAC50180.1; -; mRNA.
DR EMBL; S78996; AAB35058.1; -; mRNA.
DR EMBL; U17566; AAA74914.1; -; mRNA.
DR EMBL; U92873; AAC26162.1; -; Genomic_DNA.
DR EMBL; U92869; AAC26162.1; JOINED; Genomic_DNA.
DR EMBL; U92870; AAC26162.1; JOINED; Genomic_DNA.
DR EMBL; U92871; AAC26162.1; JOINED; Genomic_DNA.
DR EMBL; U92872; AAC26162.1; JOINED; Genomic_DNA.
DR EMBL; AF004354; AAB61417.1; -; mRNA.
DR EMBL; AK303168; BAH13909.1; -; mRNA.
DR EMBL; AK313125; BAG35945.1; -; mRNA.
DR EMBL; AL163302; CAB90483.1; ALT_SEQ; Genomic_DNA.
DR EMBL; BX322561; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471079; EAX09331.1; -; Genomic_DNA.
DR EMBL; BC003068; AAH03068.1; -; mRNA.
DR CCDS; CCDS13725.1; -. [P41440-1]
DR CCDS; CCDS56217.1; -. [P41440-2]
DR CCDS; CCDS56218.1; -. [P41440-3]
DR PIR; I38924; I38924.
DR PIR; I52728; I52728.
DR RefSeq; NP_001192135.1; NM_001205206.1. [P41440-3]
DR RefSeq; NP_001192136.1; NM_001205207.1. [P41440-2]
DR RefSeq; NP_919231.1; NM_194255.2. [P41440-1]
DR RefSeq; XP_011528002.1; XM_011529700.2. [P41440-1]
DR RefSeq; XP_011528003.1; XM_011529701.2. [P41440-1]
DR RefSeq; XP_011528004.1; XM_011529702.2. [P41440-1]
DR RefSeq; XP_011528005.1; XM_011529703.2. [P41440-1]
DR RefSeq; XP_011528006.1; XM_011529704.2.
DR RefSeq; XP_016883935.1; XM_017028446.1.
DR AlphaFoldDB; P41440; -.
DR BioGRID; 112461; 72.
DR IntAct; P41440; 9.
DR MINT; P41440; -.
DR STRING; 9606.ENSP00000308895; -.
DR BindingDB; P41440; -.
DR ChEMBL; CHEMBL4833; -.
DR DrugBank; DB11256; Levomefolic acid.
DR DrugBank; DB00563; Methotrexate.
DR DrugBank; DB06813; Pralatrexate.
DR DrugBank; DB01157; Trimetrexate.
DR DrugCentral; P41440; -.
DR GuidetoPHARMACOLOGY; 1014; -.
DR TCDB; 2.A.48.1.1; the reduced folate carrier (rfc) family.
DR GlyGen; P41440; 1 site.
DR iPTMnet; P41440; -.
DR PhosphoSitePlus; P41440; -.
DR SwissPalm; P41440; -.
DR BioMuta; SLC19A1; -.
DR DMDM; 12643280; -.
DR EPD; P41440; -.
DR jPOST; P41440; -.
DR MassIVE; P41440; -.
DR MaxQB; P41440; -.
DR PaxDb; P41440; -.
DR PeptideAtlas; P41440; -.
DR PRIDE; P41440; -.
DR ProteomicsDB; 20205; -.
DR ProteomicsDB; 55462; -. [P41440-1]
DR ProteomicsDB; 55463; -. [P41440-2]
DR Antibodypedia; 10491; 114 antibodies from 21 providers.
DR DNASU; 6573; -.
DR Ensembl; ENST00000311124.9; ENSP00000308895.4; ENSG00000173638.19. [P41440-1]
DR Ensembl; ENST00000380010.8; ENSP00000369347.4; ENSG00000173638.19. [P41440-3]
DR Ensembl; ENST00000485649.3; ENSP00000441772.1; ENSG00000173638.19. [P41440-2]
DR Ensembl; ENST00000650808.1; ENSP00000498221.1; ENSG00000173638.19. [P41440-3]
DR GeneID; 6573; -.
DR KEGG; hsa:6573; -.
DR MANE-Select; ENST00000311124.9; ENSP00000308895.4; NM_194255.4; NP_919231.1.
DR UCSC; uc002zhl.3; human. [P41440-1]
DR CTD; 6573; -.
DR DisGeNET; 6573; -.
DR GeneCards; SLC19A1; -.
DR HGNC; HGNC:10937; SLC19A1.
DR HPA; ENSG00000173638; Tissue enhanced (choroid).
DR MalaCards; SLC19A1; -.
DR MIM; 600424; gene.
DR MIM; 601775; phenotype.
DR neXtProt; NX_P41440; -.
DR OpenTargets; ENSG00000173638; -.
DR Orphanet; 565785; Methotrexate dose selection.
DR PharmGKB; PA327; -.
DR VEuPathDB; HostDB:ENSG00000173638; -.
DR eggNOG; KOG3810; Eukaryota.
DR GeneTree; ENSGT00950000183022; -.
DR HOGENOM; CLU_036909_2_0_1; -.
DR InParanoid; P41440; -.
DR OMA; YVYFGYF; -.
DR OrthoDB; 795242at2759; -.
DR PhylomeDB; P41440; -.
DR TreeFam; TF313684; -.
DR PathwayCommons; P41440; -.
DR Reactome; R-HSA-196757; Metabolism of folate and pterines.
DR SignaLink; P41440; -.
DR SIGNOR; P41440; -.
DR BioGRID-ORCS; 6573; 22 hits in 1091 CRISPR screens.
DR ChiTaRS; SLC19A1; human.
DR GeneWiki; SLC19A1; -.
DR GenomeRNAi; 6573; -.
DR Pharos; P41440; Tchem.
DR PRO; PR:P41440; -.
DR Proteomes; UP000005640; Chromosome 21.
DR RNAct; P41440; protein.
DR Bgee; ENSG00000173638; Expressed in jejunal mucosa and 151 other tissues.
DR ExpressionAtlas; P41440; baseline and differential.
DR Genevisible; P41440; HS.
DR GO; GO:0016324; C:apical plasma membrane; IDA:BHF-UCL.
DR GO; GO:0016323; C:basolateral plasma membrane; IDA:BHF-UCL.
DR GO; GO:0031526; C:brush border membrane; IEA:Ensembl.
DR GO; GO:0005887; C:integral component of plasma membrane; TAS:ProtInc.
DR GO; GO:0005886; C:plasma membrane; IDA:ARUK-UCL.
DR GO; GO:0061507; F:2',3'-cyclic GMP-AMP binding; IDA:UniProtKB.
DR GO; GO:0140360; F:cyclic-GMP-AMP transmembrane transporter activity; IDA:UniProtKB.
DR GO; GO:0008518; F:folate:anion antiporter activity; IDA:BHF-UCL.
DR GO; GO:0005542; F:folic acid binding; IBA:GO_Central.
DR GO; GO:0008517; F:folic acid transmembrane transporter activity; ISS:BHF-UCL.
DR GO; GO:0015350; F:methotrexate transmembrane transporter activity; IDA:UniProtKB.
DR GO; GO:0008514; F:organic anion transmembrane transporter activity; ISS:ARUK-UCL.
DR GO; GO:0042910; F:xenobiotic transmembrane transporter activity; ISS:ARUK-UCL.
DR GO; GO:0140361; P:cyclic-GMP-AMP transmembrane import across plasma membrane; IDA:UniProtKB.
DR GO; GO:0007565; P:female pregnancy; IEA:Ensembl.
DR GO; GO:1904447; P:folate import across plasma membrane; IDA:UniProtKB.
DR GO; GO:0098838; P:folate transmembrane transport; IDA:UniProtKB.
DR GO; GO:0046655; P:folic acid metabolic process; TAS:Reactome.
DR GO; GO:0015884; P:folic acid transport; IMP:ARUK-UCL.
DR GO; GO:0051958; P:methotrexate transport; IDA:UniProtKB.
DR GO; GO:0015711; P:organic anion transport; ISS:ARUK-UCL.
DR GO; GO:0055085; P:transmembrane transport; IBA:GO_Central.
DR GO; GO:0150104; P:transport across blood-brain barrier; TAS:ARUK-UCL.
DR GO; GO:0006855; P:xenobiotic transmembrane transport; ISS:ARUK-UCL.
DR Gene3D; 1.20.1250.20; -; 1.
DR InterPro; IPR002666; Folate_carrier.
DR InterPro; IPR036259; MFS_trans_sf.
DR InterPro; IPR028339; SLC19A1.
DR PANTHER; PTHR10686; PTHR10686; 1.
DR PANTHER; PTHR10686:SF12; PTHR10686:SF12; 1.
DR Pfam; PF01770; Folate_carrier; 1.
DR PIRSF; PIRSF028739; Folate_carrier; 1.
DR PIRSF; PIRSF500793; Folate_transporter_1; 1.
DR SUPFAM; SSF103473; SSF103473; 1.
DR TIGRFAMs; TIGR00806; rfc; 1.
PE 1: Evidence at protein level;
KW Acetylation; Alternative splicing; Antiport; Cell membrane;
KW Disease variant; Folate-binding; Glycoprotein; Hereditary hemolytic anemia;
KW Membrane; Phosphoprotein; Reference proteome; Transmembrane;
KW Transmembrane helix; Transport.
FT CHAIN 1..591
FT /note="Reduced folate transporter"
FT /id="PRO_0000178660"
FT TOPO_DOM 1..23
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305|PubMed:10347183"
FT TRANSMEM 24..44
FT /note="Helical; Name=1"
FT /evidence="ECO:0000305"
FT TOPO_DOM 45..70
FT /note="Extracellular"
FT /evidence="ECO:0000305|PubMed:10347183"
FT TRANSMEM 71..89
FT /note="Helical; Name=2"
FT /evidence="ECO:0000305"
FT TOPO_DOM 90..95
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305|PubMed:10347183"
FT TRANSMEM 96..116
FT /note="Helical; Name=3"
FT /evidence="ECO:0000305"
FT TOPO_DOM 117..123
FT /note="Extracellular"
FT /evidence="ECO:0000305|PubMed:10347183"
FT TRANSMEM 124..144
FT /note="Helical; Name=4"
FT /evidence="ECO:0000305"
FT TOPO_DOM 145..159
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305|PubMed:10347183"
FT TRANSMEM 160..177
FT /note="Helical; Name=5"
FT /evidence="ECO:0000305"
FT TOPO_DOM 178..186
FT /note="Extracellular"
FT /evidence="ECO:0000305|PubMed:10347183"
FT TRANSMEM 187..203
FT /note="Helical; Name=6"
FT /evidence="ECO:0000305"
FT TOPO_DOM 204..259
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305|PubMed:10347183"
FT TRANSMEM 260..287
FT /note="Helical; Name=7"
FT /evidence="ECO:0000305"
FT TOPO_DOM 288..309
FT /note="Extracellular"
FT /evidence="ECO:0000305|PubMed:10347183"
FT TRANSMEM 310..327
FT /note="Helical; Name=8"
FT /evidence="ECO:0000305"
FT TOPO_DOM 328..333
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305|PubMed:10347183"
FT TRANSMEM 334..354
FT /note="Helical; Name=9"
FT /evidence="ECO:0000305"
FT TOPO_DOM 355..360
FT /note="Extracellular"
FT /evidence="ECO:0000305|PubMed:10347183"
FT TRANSMEM 361..378
FT /note="Helical; Name=10"
FT /evidence="ECO:0000305"
FT TOPO_DOM 379..394
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305|PubMed:10347183"
FT TRANSMEM 395..419
FT /note="Helical; Name=11"
FT /evidence="ECO:0000305"
FT TOPO_DOM 420..433
FT /note="Extracellular"
FT /evidence="ECO:0000305|PubMed:10347183"
FT TRANSMEM 434..454
FT /note="Helical; Name=12"
FT /evidence="ECO:0000305"
FT TOPO_DOM 455..591
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305|PubMed:10347183"
FT REGION 407..419
FT /note="Required for substrate-binding"
FT /evidence="ECO:0000269|PubMed:16115875"
FT MOD_RES 1
FT /note="N-acetylmethionine"
FT /evidence="ECO:0007744|PubMed:22814378"
FT MOD_RES 5
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 225
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 474
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P41438"
FT MOD_RES 485
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P41438"
FT MOD_RES 499
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:20068231"
FT MOD_RES 503
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:20068231"
FT CARBOHYD 58
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255, ECO:0000269|PubMed:9767079"
FT VAR_SEQ 1..63
FT /note="MVPSSPAVEKQVPVEPGPDPELRSWRHLVCYLCFYGFMAQIRPGESFITPYL
FT LGPDKNFTREQ -> MRPQPAEPAPGGRGNEACSIHSE (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_042891"
FT VAR_SEQ 432..591
FT /note="FQLYSVYFLILSIIYFLGAMLDGLRHCQRGHHPRQPPAQGLRSAAEEKAAQA
FT LSVQDKGLGGLQPAQSPPLSPEDSLGAVGPASLEQRQSDPYLAQAPAPQAAEFLSPVTT
FT PSPCTLCSAQASGPEAADETCPQLAVHPPGVSKLGLQCLPSDGVQNVNQ -> NEELHV
FT ASLSLWKSHLRLAADTLSSEGSSGSGPRSWFLSPTLRAALHGPVCPSEVCPS (in
FT isoform 3)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_044497"
FT VARIANT 27
FT /note="H -> R (in dbSNP:rs1051266)"
FT /evidence="ECO:0000269|PubMed:15489334,
FT ECO:0000269|PubMed:7615551, ECO:0000269|PubMed:7641195,
FT ECO:0000269|PubMed:7826387, ECO:0000269|PubMed:9602167"
FT /id="VAR_020210"
FT VARIANT 212
FT /note="Missing (in MEGAF; loss of cellular uptake of
FT folates, including methotrexate; dbSNP:rs757838708)"
FT /evidence="ECO:0000269|PubMed:32276275"
FT /id="VAR_085516"
FT VARIANT 558
FT /note="A -> V (in dbSNP:rs35786590)"
FT /id="VAR_052404"
FT MUTAGEN 58
FT /note="N->Q: Completely abolishes N-glycosylation without
FT affecting subcellular location or folate:anion antiporter
FT activity."
FT /evidence="ECO:0000269|PubMed:9767079"
FT CONFLICT 268
FT /note="R -> P (in Ref. 1; AAA98442)"
FT /evidence="ECO:0000305"
FT CONFLICT 457
FT /note="H -> D (in Ref. 4; AAB35058)"
FT /evidence="ECO:0000305"
FT CONFLICT 483
FT /note="A -> R (in Ref. 4; AAB35058)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 591 AA; 64868 MW; 0437B1615F5517EB CRC64;
MVPSSPAVEK QVPVEPGPDP ELRSWRHLVC YLCFYGFMAQ IRPGESFITP YLLGPDKNFT
REQVTNEITP VLSYSYLAVL VPVFLLTDYL RYTPVLLLQG LSFVSVWLLL LLGHSVAHMQ
LMELFYSVTM AARIAYSSYI FSLVRPARYQ RVAGYSRAAV LLGVFTSSVL GQLLVTVGRV
SFSTLNYISL AFLTFSVVLA LFLKRPKRSL FFNRDDRGRC ETSASELERM NPGPGGKLGH
ALRVACGDSV LARMLRELGD SLRRPQLRLW SLWWVFNSAG YYLVVYYVHI LWNEVDPTTN
SARVYNGAAD AASTLLGAIT SFAAGFVKIR WARWSKLLIA GVTATQAGLV FLLAHTRHPS
SIWLCYAAFV LFRGSYQFLV PIATFQIASS LSKELCALVF GVNTFFATIV KTIITFIVSD
VRGLGLPVRK QFQLYSVYFL ILSIIYFLGA MLDGLRHCQR GHHPRQPPAQ GLRSAAEEKA
AQALSVQDKG LGGLQPAQSP PLSPEDSLGA VGPASLEQRQ SDPYLAQAPA PQAAEFLSPV
TTPSPCTLCS AQASGPEAAD ETCPQLAVHP PGVSKLGLQC LPSDGVQNVN Q
