S19A1_MOUSE
ID S19A1_MOUSE Reviewed; 512 AA.
AC P41438; Q62450; Q62451;
DT 01-NOV-1995, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1995, sequence version 1.
DT 03-AUG-2022, entry version 151.
DE RecName: Full=Reduced folate transporter {ECO:0000305};
DE AltName: Full=Intestinal folate carrier 1 {ECO:0000303|PubMed:8664315};
DE Short=IFC-1 {ECO:0000303|PubMed:8664315};
DE AltName: Full=Plasma membrane folate antiporter SLC19A1 {ECO:0000305};
DE AltName: Full=Reduced folate carrier 1 {ECO:0000303|PubMed:8276792};
DE Short=RFC-1 {ECO:0000303|PubMed:8276792, ECO:0000303|PubMed:9111015};
DE Short=RFC1 {ECO:0000303|PubMed:8276792};
DE AltName: Full=Solute carrier family 19 member 1 {ECO:0000305};
GN Name=Slc19a1 {ECO:0000312|MGI:MGI:103182};
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND FUNCTION.
RC STRAIN=DBA;
RX PubMed=8276792; DOI=10.1016/s0021-9258(17)42301-5;
RA Dixon K.H., Lanpher B.C., Chiu J., Kelly K., Cowan K.H.;
RT "A novel cDNA restores reduced folate carrier activity and methotrexate
RT sensitivity to transport deficient cells.";
RL J. Biol. Chem. 269:17-20(1994).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], AND FUNCTION.
RC STRAIN=DBA/2J; TISSUE=Intestine;
RX PubMed=8664315; DOI=10.1016/0005-2736(96)00005-3;
RA Said H.M., Nguyen T.T., Dyer D.L., Cowan K.H., Rubin S.A.;
RT "Intestinal folate transport: identification of a cDNA involved in folate
RT transport and the functional expression and distribution of its mRNA.";
RL Biochim. Biophys. Acta 1281:164-172(1996).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC STRAIN=DBA/2J;
RX PubMed=7559435; DOI=10.1074/jbc.270.39.22974;
RA Brigle K.E., Spinella M.J., Sierra E.E., Goldman I.D.;
RT "Characterization of a mutation in the reduced folate carrier in a
RT transport defective L1210 murine leukemia cell line.";
RL J. Biol. Chem. 270:22974-22979(1995).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORMS 1; 2 AND 3).
RX PubMed=9161403; DOI=10.1016/s0378-1119(96)00676-2;
RA Tolner B.M., Roy K., Sirotnak F.M.;
RT "Organization, structure and alternate splicing of the murine RFC-1 gene
RT encoding a folate transporter.";
RL Gene 189:1-7(1997).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC STRAIN=FVB/N; TISSUE=Kidney;
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 [6]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-467 AND SER-477, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19144319; DOI=10.1016/j.immuni.2008.11.006;
RA Trost M., English L., Lemieux S., Courcelles M., Desjardins M.,
RA Thibault P.;
RT "The phagosomal proteome in interferon-gamma-activated macrophages.";
RL Immunity 30:143-154(2009).
RN [7]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-472 AND SER-477, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Kidney;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [8]
RP 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 [9]
RP FUNCTION, TRANSPORTER ACTIVITY, AND BIOPHYSICOCHEMICAL PROPERTIES.
RX PubMed=9111015; DOI=10.1074/jbc.272.17.11165;
RA Chiao J.H., Roy K., Tolner B., Yang C.H., Sirotnak F.M.;
RT "RFC-1 gene expression regulates folate absorption in mouse small
RT intestine.";
RL J. Biol. Chem. 272:11165-11170(1997).
RN [10]
RP FUNCTION, TRANSPORTER ACTIVITY, AND MUTAGENESIS OF ILE-48 AND TRP-105.
RX PubMed=9748272; DOI=10.1074/jbc.273.40.25953;
RA Tse A., Brigle K., Taylor S.M., Moran R.G.;
RT "Mutations in the reduced folate carrier gene which confer dominant
RT resistance to 5,10-dideazatetrahydrofolate.";
RL J. Biol. Chem. 273:25953-25960(1998).
RN [11]
RP LACK OF CYCLIC DINUCLEOTIDE 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).
CC -!- FUNCTION: Antiporter that mediates the import of reduced folates
CC (PubMed:8276792, PubMed:8664315, PubMed:9111015, PubMed:9748272).
CC Mechanistically, acts as a secondary active transporter, which exports
CC intracellular organic anions down their concentration gradients to
CC facilitate the uptake of its substrates (By similarity). Has high
CC affinity for N5-methyltetrahydrofolate, the predominant circulating
CC form of folate (PubMed:8276792, PubMed:9111015). Also able to mediate
CC the import of antifolate drug methotrexate (PubMed:8276792,
CC PubMed:8664315, PubMed:9748272). 5-amino-4-imidazolecarboxamide
CC riboside (AICAR), when phosphorylated to AICAR monophosphate, can serve
CC as an organic anion for antiporter activity (By similarity).
CC {ECO:0000250|UniProtKB:P41440, ECO:0000269|PubMed:8276792,
CC ECO:0000269|PubMed:8664315, ECO:0000269|PubMed:9111015,
CC ECO:0000269|PubMed:9748272}.
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:9111015, ECO:0000269|PubMed:9748272};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:60461;
CC Evidence={ECO:0000269|PubMed:9111015, ECO:0000269|PubMed:9748272};
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=1.8 uM for N5-methyltetrahydrofolate (at pH 6.2)
CC {ECO:0000269|PubMed:9111015};
CC KM=2.3 uM for N5-methyltetrahydrofolate (at pH 7.4)
CC {ECO:0000269|PubMed:9111015};
CC Vmax=0.8 pmol/min/mg enzyme with N5-methyltetrahydrofolate as
CC substrate (at pH 6.2) {ECO:0000269|PubMed:9111015};
CC Vmax=0.2 pmol/min/mg enzyme with N5-methyltetrahydrofolate as
CC substrate (at pH 7.4) {ECO:0000269|PubMed:9111015};
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:10787414};
CC Multi-pass membrane protein {ECO:0000255}. Apical cell membrane
CC {ECO:0000269|PubMed:10787414}; Multi-pass membrane protein
CC {ECO:0000255}. Basolateral cell membrane
CC {ECO:0000250|UniProtKB:P41440}; Multi-pass membrane protein
CC {ECO:0000255}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=P41438-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P41438-2; Sequence=VSP_006125;
CC Name=3;
CC IsoId=P41438-3; Sequence=VSP_006126, VSP_006127;
CC -!- SIMILARITY: Belongs to the reduced folate carrier (RFC) transporter (TC
CC 2.A.48) family. {ECO:0000305}.
CC -!- CAUTION: In contrast to human, not able to transport immunoreactive
CC cyclic dinucleotides, such as cyclic GMP-AMP (2'-3'-cGAMP), an immune
CC messenger produced in response to DNA virus in the cytosol.
CC {ECO:0000269|PubMed:31511694}.
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DR EMBL; L36539; AAB38483.1; -; mRNA.
DR EMBL; L23755; AAA39738.1; -; mRNA.
DR EMBL; U32469; AAC52258.1; -; mRNA.
DR EMBL; U66103; AAC53287.1; -; mRNA.
DR EMBL; U57784; AAC53288.1; -; Genomic_DNA.
DR EMBL; U57781; AAC53288.1; JOINED; Genomic_DNA.
DR EMBL; U57782; AAC53288.1; JOINED; Genomic_DNA.
DR EMBL; U57783; AAC53288.1; JOINED; Genomic_DNA.
DR EMBL; U57785; AAC53289.1; -; Genomic_DNA.
DR EMBL; U57781; AAC53289.1; JOINED; Genomic_DNA.
DR EMBL; U57782; AAC53289.1; JOINED; Genomic_DNA.
DR EMBL; U57783; AAC53289.1; JOINED; Genomic_DNA.
DR EMBL; U57785; AAC53290.1; -; Genomic_DNA.
DR EMBL; U57781; AAC53290.1; JOINED; Genomic_DNA.
DR EMBL; U57782; AAC53290.1; JOINED; Genomic_DNA.
DR EMBL; U57783; AAC53290.1; JOINED; Genomic_DNA.
DR EMBL; U57784; AAC53290.1; JOINED; Genomic_DNA.
DR EMBL; U57785; AAC53291.1; -; Genomic_DNA.
DR EMBL; U57781; AAC53291.1; JOINED; Genomic_DNA.
DR EMBL; U57782; AAC53291.1; JOINED; Genomic_DNA.
DR EMBL; U57783; AAC53291.1; JOINED; Genomic_DNA.
DR EMBL; BC015263; AAH15263.1; -; mRNA.
DR CCDS; CCDS35947.1; -. [P41438-1]
DR PIR; A53092; A53092.
DR RefSeq; NP_001186200.1; NM_001199271.1. [P41438-1]
DR RefSeq; NP_112473.1; NM_031196.3. [P41438-1]
DR RefSeq; XP_006513477.1; XM_006513414.3. [P41438-1]
DR RefSeq; XP_006513478.1; XM_006513415.3. [P41438-1]
DR RefSeq; XP_006513479.1; XM_006513416.2. [P41438-1]
DR RefSeq; XP_006513480.1; XM_006513417.2. [P41438-1]
DR RefSeq; XP_006513481.1; XM_006513418.3.
DR AlphaFoldDB; P41438; -.
DR STRING; 10090.ENSMUSP00000101050; -.
DR iPTMnet; P41438; -.
DR PhosphoSitePlus; P41438; -.
DR SwissPalm; P41438; -.
DR EPD; P41438; -.
DR jPOST; P41438; -.
DR MaxQB; P41438; -.
DR PaxDb; P41438; -.
DR PeptideAtlas; P41438; -.
DR PRIDE; P41438; -.
DR ProteomicsDB; 253354; -. [P41438-1]
DR ProteomicsDB; 253355; -. [P41438-2]
DR ProteomicsDB; 253356; -. [P41438-3]
DR Antibodypedia; 10491; 114 antibodies from 21 providers.
DR DNASU; 20509; -.
DR Ensembl; ENSMUST00000105410; ENSMUSP00000101050; ENSMUSG00000001436. [P41438-1]
DR Ensembl; ENSMUST00000144234; ENSMUSP00000116784; ENSMUSG00000001436. [P41438-1]
DR GeneID; 20509; -.
DR KEGG; mmu:20509; -.
DR UCSC; uc007fvc.2; mouse. [P41438-1]
DR CTD; 6573; -.
DR MGI; MGI:103182; Slc19a1.
DR VEuPathDB; HostDB:ENSMUSG00000001436; -.
DR eggNOG; KOG3810; Eukaryota.
DR GeneTree; ENSGT00950000183022; -.
DR HOGENOM; CLU_036909_2_0_1; -.
DR InParanoid; P41438; -.
DR OMA; YVYFGYF; -.
DR PhylomeDB; P41438; -.
DR TreeFam; TF313684; -.
DR Reactome; R-MMU-196757; Metabolism of folate and pterines.
DR BioGRID-ORCS; 20509; 5 hits in 73 CRISPR screens.
DR ChiTaRS; Slc19a1; mouse.
DR PRO; PR:P41438; -.
DR Proteomes; UP000000589; Chromosome 10.
DR RNAct; P41438; protein.
DR Bgee; ENSMUSG00000001436; Expressed in paneth cell and 271 other tissues.
DR ExpressionAtlas; P41438; baseline and differential.
DR Genevisible; P41438; MM.
DR GO; GO:0016324; C:apical plasma membrane; IDA:BHF-UCL.
DR GO; GO:0016323; C:basolateral plasma membrane; ISO:MGI.
DR GO; GO:0031526; C:brush border membrane; ISO:MGI.
DR GO; GO:0005887; C:integral component of plasma membrane; IEA:InterPro.
DR GO; GO:0005886; C:plasma membrane; ISO:MGI.
DR GO; GO:0061507; F:2',3'-cyclic GMP-AMP binding; ISO:MGI.
DR GO; GO:0008518; F:folate:anion antiporter activity; ISO:MGI.
DR GO; GO:0005542; F:folic acid binding; ISO:MGI.
DR GO; GO:0008517; F:folic acid transmembrane transporter activity; IDA:UniProtKB.
DR GO; GO:0015350; F:methotrexate transmembrane transporter activity; IDA:UniProtKB.
DR GO; GO:0008514; F:organic anion transmembrane transporter activity; ISO:MGI.
DR GO; GO:0042910; F:xenobiotic transmembrane transporter activity; ISO:MGI.
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:0015884; P:folic acid transport; ISO:MGI.
DR GO; GO:0051958; P:methotrexate transport; IDA:UniProtKB.
DR GO; GO:0015711; P:organic anion transport; ISO:MGI.
DR GO; GO:0055085; P:transmembrane transport; IBA:GO_Central.
DR GO; GO:0006855; P:xenobiotic transmembrane transport; ISO:MGI.
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; Folate-binding;
KW Membrane; Phosphoprotein; Reference proteome; Transmembrane;
KW Transmembrane helix; Transport.
FT CHAIN 1..512
FT /note="Reduced folate transporter"
FT /id="PRO_0000178661"
FT TOPO_DOM 1..27
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:P41440"
FT TRANSMEM 28..48
FT /note="Helical; Name=1"
FT /evidence="ECO:0000255"
FT TOPO_DOM 49..64
FT /note="Extracellular"
FT /evidence="ECO:0000250|UniProtKB:P41440"
FT TRANSMEM 65..85
FT /note="Helical; Name=2"
FT /evidence="ECO:0000255"
FT TOPO_DOM 86..91
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:P41440"
FT TRANSMEM 92..112
FT /note="Helical; Name=3"
FT /evidence="ECO:0000255"
FT TOPO_DOM 113..121
FT /note="Extracellular"
FT /evidence="ECO:0000250|UniProtKB:P41440"
FT TRANSMEM 122..142
FT /note="Helical; Name=4"
FT /evidence="ECO:0000255"
FT TOPO_DOM 143..155
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:P41440"
FT TRANSMEM 156..176
FT /note="Helical; Name=5"
FT /evidence="ECO:0000255"
FT TOPO_DOM 177..180
FT /note="Extracellular"
FT /evidence="ECO:0000250|UniProtKB:P41440"
FT TRANSMEM 181..201
FT /note="Helical; Name=6"
FT /evidence="ECO:0000255"
FT TOPO_DOM 202..271
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:P41440"
FT TRANSMEM 272..292
FT /note="Helical; Name=7"
FT /evidence="ECO:0000255"
FT TOPO_DOM 293..304
FT /note="Extracellular"
FT /evidence="ECO:0000250|UniProtKB:P41440"
FT TRANSMEM 305..325
FT /note="Helical; Name=8"
FT /evidence="ECO:0000255"
FT TOPO_DOM 326..329
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:P41440"
FT TRANSMEM 330..350
FT /note="Helical; Name=9"
FT /evidence="ECO:0000255"
FT TOPO_DOM 351..354
FT /note="Extracellular"
FT /evidence="ECO:0000250|UniProtKB:P41440"
FT TRANSMEM 355..375
FT /note="Helical; Name=10"
FT /evidence="ECO:0000255"
FT TOPO_DOM 376..390
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:P41440"
FT TRANSMEM 391..411
FT /note="Helical; Name=11"
FT /evidence="ECO:0000255"
FT TOPO_DOM 412..426
FT /note="Extracellular"
FT /evidence="ECO:0000250|UniProtKB:P41440"
FT TRANSMEM 427..447
FT /note="Helical; Name=12"
FT /evidence="ECO:0000255"
FT TOPO_DOM 448..512
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:P41440"
FT REGION 400..412
FT /note="Required for substrate-binding"
FT /evidence="ECO:0000250|UniProtKB:P41440"
FT REGION 478..512
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 496..512
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 1
FT /note="N-acetylmethionine"
FT /evidence="ECO:0000250|UniProtKB:P41440"
FT MOD_RES 467
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:19144319"
FT MOD_RES 472
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 477
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:19144319,
FT ECO:0007744|PubMed:21183079"
FT VAR_SEQ 273..313
FT /note="WWVFNSSGYYLITYYVHVLWRSTDSSLSYNGAVDAASTLLS -> C (in
FT isoform 2)"
FT /evidence="ECO:0000303|PubMed:9161403"
FT /id="VSP_006125"
FT VAR_SEQ 378..379
FT /note="FQ -> PS (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:9161403"
FT /id="VSP_006126"
FT VAR_SEQ 380..512
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:9161403"
FT /id="VSP_006127"
FT MUTAGEN 48
FT /note="I->F: Induces resistance to 5,10-
FT dideazatetrahydrofolate; when associated with G-105."
FT /evidence="ECO:0000269|PubMed:9748272"
FT MUTAGEN 105
FT /note="W->G: Induces resistance to 5,10-
FT dideazatetrahydrofolate; when associated with F-48."
FT /evidence="ECO:0000269|PubMed:9748272"
SQ SEQUENCE 512 AA; 58150 MW; 640CB7AD2624BF67 CRC64;
MVPTGQVAEK QAYEEPRQDH ELKSWRCLVF YLCFFGFMAQ LRPGESFITP FLLERKFTKE
QVTNEIIPML PYSHLAVLVP VFLLTDYLRY KPVLVLQCLS FVCVWLLLLL GTSVVHMQLM
EVFYSVTMAA RIAYSSYIFS LVHPSRYQRM ASYSRAAVLL GVFISSVLGQ ALVTVGHIST
YTLNCVSLGF ILFSLVLSLF LKRPKRSLFF NRSTLARGAL PCELDQMHPG PDRPETRKLD
RMLGTCRDSF LVRMLSELVE NARQPQLRLW CLWWVFNSSG YYLITYYVHV LWRSTDSSLS
YNGAVDAAST LLSAITSFSA GFLSIRWTLW SKLVIAGVIA IQASLVFCMF QIRDIWVCYV
TFVLFRGAYQ FLVPIATFQI ASSLSKELCA LVFGINTFLA TALKTCITLV VSDKRGLGLQ
VRDQFRIYFI YFLMLSITCF AWAGLDGLRY CQRGRHQPLA QAQELRSPLE TSVQAISLQD
GDLRGPQPSA PQLLSEDGME DDRGDLRVEA KA
