ID PCFT_HUMAN Reviewed; 459 AA. AC Q96NT5; Q1HE20; Q86T92; Q8TEG3; Q96FL0; DT 08-NOV-2005, integrated into UniProtKB/Swiss-Prot. DT 01-DEC-2001, sequence version 1. DT 12-AUG-2020, entry version 156. DE RecName: Full=Proton-coupled folate transporter; DE AltName: Full=G21; DE AltName: Full=Heme carrier protein 1; DE AltName: Full=PCFT/HCP1; DE AltName: Full=Solute carrier family 46 member 1; GN Name=SLC46A1; Synonyms=HCP1, PCFT; 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 [LARGE SCALE MRNA] (ISOFORM 1), AND NUCLEOTIDE SEQUENCE RP [LARGE SCALE MRNA] OF 269-459 (ISOFORM 2). RC TISSUE=Glial tumor, and Spleen; 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 [2] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RG NIEHS SNPs program; RL Submitted (APR-2006) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). RC TISSUE=Eye; 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 [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 199-459 (ISOFORM 1). RC TISSUE=Spinal cord; RX PubMed=17974005; DOI=10.1186/1471-2164-8-399; RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U., RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D., RA Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A., RA Wiemann S., Schupp I.; RT "The full-ORF clone resource of the German cDNA consortium."; RL BMC Genomics 8:399-399(2007). RN [5] RP SUBCELLULAR LOCATION. RX PubMed=16143108; DOI=10.1016/j.cell.2005.06.025; RA Shayeghi M., Latunde-Dada G.O., Oakhill J.S., Laftah A.H., Takeuchi K., RA Halliday N., Khan Y., Warley A., McCann F.E., Hider R.C., Frazer D.M., RA Anderson G.J., Vulpe C.D., Simpson R.J., McKie A.T.; RT "Identification of an intestinal heme transporter."; RL Cell 122:789-801(2005). RN [6] RP FUNCTION, BIOPHYSICOCHEMICAL PROPERTIES, SUBCELLULAR LOCATION, TISSUE RP SPECIFICITY, AND INVOLVEMENT IN HFM. RX PubMed=17129779; DOI=10.1016/j.cell.2006.09.041; RA Qiu A., Jansen M., Sakaris A., Min S.H., Chattopadhyay S., Tsai E., RA Sandoval C., Zhao R., Akabas M.H., Goldman I.D.; RT "Identification of an intestinal folate transporter and the molecular basis RT for hereditary folate malabsorption."; RL Cell 127:917-928(2006). RN [7] RP FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=17156779; DOI=10.1016/j.febslet.2006.11.048; RA Latunde-Dada G.O., Takeuchi K., Simpson R.J., McKie A.T.; RT "Haem carrier protein 1 (HCP1): expression and functional studies in RT cultured cells."; RL FEBS Lett. 580:6865-6870(2006). RN [8] RP FUNCTION, SUBCELLULAR LOCATION, AND VARIANTS HFM SER-113; ARG-147; ARG-318; RP TRP-376 AND ARG-425. RX PubMed=17446347; DOI=10.1182/blood-2007-02-077099; RA Zhao R., Min S.H., Qiu A., Sakaris A., Goldberg G.L., Sandoval C., RA Malatack J.J., Rosenblatt D.S., Goldman I.D.; RT "The spectrum of mutations in the PCFT gene, coding for an intestinal RT folate transporter, that are the basis for hereditary folate RT malabsorption."; RL Blood 110:1147-1152(2007). RN [9] RP TISSUE SPECIFICITY. RX PubMed=17335806; DOI=10.1016/j.yexcr.2007.01.019; RA Sharma S., Dimasi D., Broeer S., Kumar R., Della N.G.; RT "Heme carrier protein 1 (HCP1) expression and functional analysis in the RT retina and retinal pigment epithelium."; RL Exp. Cell Res. 313:1251-1259(2007). RN [10] RP FUNCTION, BIOPHYSICOCHEMICAL PROPERTIES, AND SUBCELLULAR LOCATION. RX PubMed=17475902; DOI=10.1124/jpet.107.122606; RA Nakai Y., Inoue K., Abe N., Hatakeyama M., Ohta K.-Y., Otagiri M., RA Hayashi Y., Yuasa H.; RT "Functional characterization of human proton-coupled folate RT transporter/heme carrier protein 1 heterologously expressed in mammalian RT cells as a folate transporter."; RL J. Pharmacol. Exp. Ther. 322:469-476(2007). RN [11] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007; RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R., RA Greff Z., Keri G., Stemmann O., Mann M.; RT "Kinase-selective enrichment enables quantitative phosphoproteomics of the RT kinome across the cell cycle."; RL Mol. Cell 31:438-448(2008). RN [12] 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 [13] RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-58. RC TISSUE=Liver; RX PubMed=19159218; DOI=10.1021/pr8008012; RA Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H.; RT "Glycoproteomics analysis of human liver tissue by combination of multiple RT enzyme digestion and hydrazide chemistry."; RL J. Proteome Res. 8:651-661(2009). RN [14] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-458, AND IDENTIFICATION BY RP 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 [15] 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 [16] RP SUBUNIT, AND SUBCELLULAR LOCATION. RX PubMed=23601781; DOI=10.1111/febs.12293; RA Duddempudi P.K., Nakashe P., Blanton M.P., Jansen M.; RT "The monomeric state of the proton-coupled folate transporter represents RT the functional unit in the plasma membrane."; RL FEBS J. 280:2900-2915(2013). RN [17] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-6 AND SER-458, 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 [18] RP SUBCELLULAR LOCATION, TOPOLOGY, AND GLYCOSYLATION AT ASN-58 AND ASN-68. RX PubMed=25053408; DOI=10.1074/jbc.m114.578252; RA Wilson M.R., Hou Z., Matherly L.H.; RT "Substituted cysteine accessibility reveals a novel transmembrane 2-3 RT reentrant loop and functional role for transmembrane domain 2 in the human RT proton-coupled folate transporter."; RL J. Biol. Chem. 289:25287-25295(2014). RN [19] RP VARIANT HFM CYS-113, AND CHARACTERIZATION OF VARIANT HFM CYS-113. RX PubMed=18559978; DOI=10.1182/blood-2008-04-150276; RA Lasry I., Berman B., Straussberg R., Sofer Y., Bessler H., Sharkia M., RA Glaser F., Jansen G., Drori S., Assaraf Y.G.; RT "A novel loss-of-function mutation in the proton-coupled folate transporter RT from a patient with hereditary folate malabsorption reveals that Arg 113 is RT crucial for function."; RL Blood 112:2055-2061(2008). RN [20] RP VARIANT HFM GLN-376, CHARACTERIZATION OF VARIANT HFM GLN-376, AND RP MUTAGENESIS OF ARG-376. RX PubMed=20686069; DOI=10.1152/ajpcell.00113.2010; RA Mahadeo K., Diop-Bove N., Shin D., Unal E.S., Teo J., Zhao R., Chang M.H., RA Fulterer A., Romero M.F., Goldman I.D.; RT "Properties of the Arg376 residue of the proton-coupled folate transporter RT (PCFT-SLC46A1) and a glutamine mutant causing hereditary folate RT malabsorption."; RL Am. J. Physiol. 299:C1153-C1161(2010). RN [21] RP VARIANT HFM TYR-156, CHARACTERIZATION OF VARIANT HFM TYR-156, AND RP MUTAGENESIS OF ASP-109 AND ASP-156. RX PubMed=20805364; DOI=10.1182/blood-2010-06-291237; RA Shin D.S., Min S.H., Russell L., Zhao R., Fiser A., Goldman I.D.; RT "Functional roles of aspartate residues of the proton-coupled folate RT transporter (PCFT-SLC46A1); a D156Y mutation causing hereditary folate RT malabsorption."; RL Blood 116:5162-5169(2010). RN [22] RP VARIANTS HFM ASP-335 AND ARG-338, AND CHARACTERIZATION OF VARIANTS HFM RP ASP-335 AND ARG-338. RX PubMed=21333572; DOI=10.1016/j.ymgme.2011.01.008; RA Shin D.S., Mahadeo K., Min S.H., Diop-Bove N., Clayton P., Zhao R., RA Goldman I.D.; RT "Identification of novel mutations in the proton-coupled folate transporter RT (PCFT-SLC46A1) associated with hereditary folate malabsorption."; RL Mol. Genet. Metab. 103:33-37(2011). CC -!- FUNCTION: Has been shown to act both as an intestinal proton-coupled CC high-affinity folate transporter and as an intestinal heme transporter CC which mediates heme uptake from the gut lumen into duodenal epithelial CC cells. The iron is then released from heme and may be transported into CC the bloodstream. Dietary heme iron is an important nutritional source CC of iron. Shows a higher affinity for folate than heme. CC {ECO:0000269|PubMed:17129779, ECO:0000269|PubMed:17156779, CC ECO:0000269|PubMed:17446347, ECO:0000269|PubMed:17475902}. CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC Kinetic parameters: CC KM=1.3 uM for folic acid (at pH 5.5) {ECO:0000269|PubMed:17129779, CC ECO:0000269|PubMed:17475902}; CC KM=1.5 uM for folic acid (at pH 6.0) {ECO:0000269|PubMed:17129779, CC ECO:0000269|PubMed:17475902}; CC KM=2.7 uM for folic acid (at pH 6.5) {ECO:0000269|PubMed:17129779, CC ECO:0000269|PubMed:17475902}; CC KM=6.0 uM for folic acid (at pH 7.0) {ECO:0000269|PubMed:17129779, CC ECO:0000269|PubMed:17475902}; CC KM=56.2 uM for folic acid (at pH 7.5) {ECO:0000269|PubMed:17129779, CC ECO:0000269|PubMed:17475902}; CC pH dependence: CC Optimum pH is 4.0-5.5. Activity decreases above pH 5.5 and reaches CC negligible levels at neutral pH and above. CC {ECO:0000269|PubMed:17129779, ECO:0000269|PubMed:17475902}; CC -!- SUBUNIT: Monomer. {ECO:0000269|PubMed:23601781}. CC -!- SUBCELLULAR LOCATION: Apical cell membrane; Multi-pass membrane CC protein. Cytoplasm {ECO:0000250}. Note=Localizes to the apical membrane CC of intestinal cells in iron-deficient cells, while it resides in the CC cytoplasm in iron-replete cells. {ECO:0000250}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=Q96NT5-1; Sequence=Displayed; CC Name=2; CC IsoId=Q96NT5-2; Sequence=VSP_016053; CC -!- TISSUE SPECIFICITY: Expressed in kidney, liver, placenta, small CC intestine, spleen, retina and retinal pigment epithelium. Lower levels CC found in colon and testis. Very low levels in brain, lung, stomach, CC heart and muscle. In intestine, expressed in duodenum with lower levels CC in jejunum, ileum, cecum, rectum and segments of the colon. CC {ECO:0000269|PubMed:17129779, ECO:0000269|PubMed:17335806}. CC -!- DISEASE: Hereditary folate malabsorption (HFM) [MIM:229050]: Rare CC autosomal recessive disorder characterized by impaired intestinal CC folate absorption with folate deficiency resulting in anemia, CC hypoimmunoglobulinemia with recurrent infections, and recurrent or CC chronic diarrhea. In many patients, neurological abnormalities such as CC seizures or mental retardation become apparent during early childhood, CC attributed to impaired transport of folates into the central nervous CC system. When diagnosed early, the disorder can be treated by CC administration of folate. If untreated, it can be fatal and, if CC treatment is delayed, the neurological defects can become permanent. CC {ECO:0000269|PubMed:17129779, ECO:0000269|PubMed:17446347, CC ECO:0000269|PubMed:18559978, ECO:0000269|PubMed:20686069, CC ECO:0000269|PubMed:20805364, ECO:0000269|PubMed:21333572}. Note=The CC disease is caused by mutations affecting the gene represented in this CC entry. CC -!- MISCELLANEOUS: [Isoform 2]: Inactive isoform which results in impaired CC folate absorption, giving rise to hereditary folate malabsorption CC (HFM). {ECO:0000305}. CC -!- SIMILARITY: Belongs to the major facilitator superfamily. SLC46A CC family. {ECO:0000305}. CC -!- WEB RESOURCE: Name=Mendelian genes solute carrier family 46 (folate CC transporter), member 1 (SLC46A1); Note=Leiden Open Variation Database CC (LOVD); CC URL="http://www.lovd.nl/SLC46A1"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AK054669; BAB70789.1; -; mRNA. DR EMBL; AK074161; BAB84987.1; -; mRNA. DR EMBL; DQ496103; ABF47092.1; -; Genomic_DNA. DR EMBL; BC010691; AAH10691.1; -; mRNA. DR EMBL; AL832613; CAD89945.1; -; mRNA. DR CCDS; CCDS74019.1; -. [Q96NT5-2] DR CCDS; CCDS74020.1; -. [Q96NT5-1] DR RefSeq; NP_001229295.1; NM_001242366.2. [Q96NT5-2] DR RefSeq; NP_542400.2; NM_080669.5. [Q96NT5-1] DR BioGRID; 125236; 2. DR IntAct; Q96NT5; 3. DR MINT; Q96NT5; -. DR STRING; 9606.ENSP00000480703; -. DR BindingDB; Q96NT5; -. DR ChEMBL; CHEMBL1795188; -. DR DrugBank; DB08878; Aminopterin. DR DrugBank; DB00158; Folic acid. DR DrugBank; DB11256; Levomefolic acid. DR DrugBank; DB00563; Methotrexate. DR DrugBank; DB00795; Sulfasalazine. DR DrugCentral; Q96NT5; -. DR GuidetoPHARMACOLOGY; 1213; -. DR TCDB; 2.A.1.50.1; the major facilitator superfamily (mfs). DR GlyGen; Q96NT5; 2 sites. DR iPTMnet; Q96NT5; -. DR PhosphoSitePlus; Q96NT5; -. DR SwissPalm; Q96NT5; -. DR BioMuta; SLC46A1; -. DR DMDM; 74732636; -. DR jPOST; Q96NT5; -. DR MassIVE; Q96NT5; -. DR MaxQB; Q96NT5; -. DR PaxDb; Q96NT5; -. DR PeptideAtlas; Q96NT5; -. DR PRIDE; Q96NT5; -. DR ProteomicsDB; 77556; -. [Q96NT5-1] DR ProteomicsDB; 77557; -. [Q96NT5-2] DR Antibodypedia; 26300; 109 antibodies. DR DNASU; 113235; -. DR Ensembl; ENST00000612814; ENSP00000480703; ENSG00000076351. [Q96NT5-1] DR Ensembl; ENST00000618626; ENSP00000483652; ENSG00000076351. [Q96NT5-2] DR GeneID; 113235; -. DR KEGG; hsa:113235; -. DR UCSC; uc032ezi.2; human. [Q96NT5-1] DR CTD; 113235; -. DR DisGeNET; 113235; -. DR EuPathDB; HostDB:ENSG00000076351.12; -. DR GeneCards; SLC46A1; -. DR GeneReviews; SLC46A1; -. DR HGNC; HGNC:30521; SLC46A1. DR HPA; ENSG00000076351; Tissue enhanced (intestine). DR MalaCards; SLC46A1; -. DR MIM; 229050; phenotype. DR MIM; 611672; gene. DR neXtProt; NX_Q96NT5; -. DR OpenTargets; ENSG00000076351; -. DR Orphanet; 90045; Hereditary folate malabsorption. DR PharmGKB; PA162403775; -. DR eggNOG; KOG2816; Eukaryota. DR GeneTree; ENSGT00950000183096; -. DR InParanoid; Q96NT5; -. DR KO; K14613; -. DR OMA; WDSRLIG; -. DR OrthoDB; 17940at2759; -. DR PhylomeDB; Q96NT5; -. DR TreeFam; TF315701; -. DR PathwayCommons; Q96NT5; -. DR Reactome; R-HSA-196757; Metabolism of folate and pterines. DR Reactome; R-HSA-917937; Iron uptake and transport. DR SIGNOR; Q96NT5; -. DR BioGRID-ORCS; 113235; 2 hits in 124 CRISPR screens. DR ChiTaRS; SLC46A1; human. DR GeneWiki; SLC46A1; -. DR GenomeRNAi; 113235; -. DR Pharos; Q96NT5; Tchem. DR PRO; PR:Q96NT5; -. DR Proteomes; UP000005640; Chromosome 17. DR RNAct; Q96NT5; protein. DR Bgee; ENSG00000076351; Expressed in duodenum and 178 other tissues. DR ExpressionAtlas; Q96NT5; baseline and differential. DR Genevisible; Q96NT5; HS. DR GO; GO:0016324; C:apical plasma membrane; IDA:UniProtKB. DR GO; GO:0031526; C:brush border membrane; IEA:Ensembl. DR GO; GO:0009986; C:cell surface; HDA:UniProtKB. DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB. DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW. DR GO; GO:0005886; C:plasma membrane; IDA:BHF-UCL. DR GO; GO:0005542; F:folic acid binding; IEA:UniProtKB-KW. DR GO; GO:0008517; F:folic acid transmembrane transporter activity; IDA:UniProtKB. DR GO; GO:0015232; F:heme transporter activity; TAS:Reactome. DR GO; GO:0015350; F:methotrexate transmembrane transporter activity; IC:BHF-UCL. DR GO; GO:0015078; F:proton transmembrane transporter activity; IDA:BHF-UCL. DR GO; GO:0006879; P:cellular iron ion homeostasis; TAS:Reactome. DR GO; GO:1904447; P:folate import across plasma membrane; IDA:BHF-UCL. DR GO; GO:0046655; P:folic acid metabolic process; TAS:Reactome. DR GO; GO:0015884; P:folic acid transport; IDA:UniProtKB. DR GO; GO:0098829; P:intestinal folate absorption; IC:BHF-UCL. DR GO; GO:0051958; P:methotrexate transport; IDA:BHF-UCL. DR GO; GO:1902600; P:proton transmembrane transport; IDA:BHF-UCL. DR InterPro; IPR011701; MFS. DR InterPro; IPR020846; MFS_dom. DR InterPro; IPR036259; MFS_trans_sf. DR InterPro; IPR005829; Sugar_transporter_CS. DR Pfam; PF07690; MFS_1; 1. DR SUPFAM; SSF103473; SSF103473; 1. DR PROSITE; PS50850; MFS; 1. PE 1: Evidence at protein level; KW Acetylation; Alternative splicing; Cell membrane; Cytoplasm; KW Disease mutation; Folate-binding; Glycoprotein; Membrane; Phosphoprotein; KW Polymorphism; Reference proteome; Transmembrane; Transmembrane helix; KW Transport. FT CHAIN 1..459 FT /note="Proton-coupled folate transporter" FT /id="PRO_0000084851" FT TOPO_DOM 1..24 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 25..48 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 49..84 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 85..107 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 108..113 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 114..137 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 138..145 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 146..168 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 169..180 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 181..203 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 204..212 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 213..236 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 237..265 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 266..288 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 289..309 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 310..328 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 329..331 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 332..356 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 357..359 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 360..381 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 382..393 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 394..412 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 413..424 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 425..449 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 450..459 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT MOD_RES 1 FT /note="N-acetylmethionine" FT /evidence="ECO:0000244|PubMed:22814378" FT MOD_RES 6 FT /note="Phosphoserine" FT /evidence="ECO:0000244|PubMed:23186163" FT MOD_RES 458 FT /note="Phosphoserine" FT /evidence="ECO:0000244|PubMed:20068231, FT ECO:0000244|PubMed:23186163" FT CARBOHYD 58 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:19159218, FT ECO:0000269|PubMed:25053408" FT CARBOHYD 68 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:25053408" FT VAR_SEQ 361..388 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:14702039, FT ECO:0000303|PubMed:15489334" FT /id="VSP_016053" FT VARIANT 113 FT /note="R -> C (in HFM; loss-of-function mutation; targeted FT to the plasma membrane but has significantly impaired FT folate transport activity; dbSNP:rs80338770)" FT /evidence="ECO:0000269|PubMed:18559978" FT /id="VAR_058210" FT VARIANT 113 FT /note="R -> S (in HFM; abolishes folate uptake; FT dbSNP:rs80338770)" FT /evidence="ECO:0000269|PubMed:17446347" FT /id="VAR_032825" FT VARIANT 147 FT /note="G -> R (in HFM; reduces folate uptake to 13% of FT normal levels; dbSNP:rs80338771)" FT /evidence="ECO:0000269|PubMed:17446347" FT /id="VAR_032826" FT VARIANT 156 FT /note="D -> Y (in HFM; loss of function measured as FT methotrexate uptake; dbSNP:rs281875210)" FT /evidence="ECO:0000269|PubMed:20805364" FT /id="VAR_067960" FT VARIANT 295 FT /note="T -> A (in dbSNP:rs34552966)" FT /id="VAR_050302" FT VARIANT 318 FT /note="S -> R (in HFM; abolishes folate uptake; FT dbSNP:rs80338772)" FT /evidence="ECO:0000269|PubMed:17446347" FT /id="VAR_032827" FT VARIANT 335 FT /note="A -> D (in HFM; loss of function measured as FT methotrexate uptake; dbSNP:rs281875208)" FT /evidence="ECO:0000269|PubMed:21333572" FT /id="VAR_067961" FT VARIANT 338 FT /note="G -> R (in HFM; loss of function measured as FT methotrexate uptake; dbSNP:rs281875209)" FT /evidence="ECO:0000269|PubMed:21333572" FT /id="VAR_067962" FT VARIANT 376 FT /note="R -> Q (in HFM; abolishes folate uptake; FT dbSNP:rs281875211)" FT /evidence="ECO:0000269|PubMed:20686069" FT /id="VAR_067963" FT VARIANT 376 FT /note="R -> W (in HFM; abolishes folate uptake; FT dbSNP:rs80338773)" FT /evidence="ECO:0000269|PubMed:17446347" FT /id="VAR_032828" FT VARIANT 425 FT /note="P -> R (in HFM; reduces folate uptake to 3.5% of FT normal levels; dbSNP:rs80338774)" FT /evidence="ECO:0000269|PubMed:17446347" FT /id="VAR_032829" FT MUTAGEN 109 FT /note="D->A,G,E,K,N,S: Loss of methotrexate uptake." FT /evidence="ECO:0000269|PubMed:20805364" FT MUTAGEN 156 FT /note="D->E: Does not affect methotrexate uptake." FT /evidence="ECO:0000269|PubMed:20805364" FT MUTAGEN 156 FT /note="D->F,K,N,V,W: Loss of methotrexate uptake." FT /evidence="ECO:0000269|PubMed:20805364" FT MUTAGEN 156 FT /note="D->G: 2-fold reduction of methotrexate uptake." FT /evidence="ECO:0000269|PubMed:20805364" FT MUTAGEN 156 FT /note="D->S: 8-fold reduction of methotrexate uptake." FT /evidence="ECO:0000269|PubMed:20805364" FT MUTAGEN 376 FT /note="R->A,C,E,H,Q,W: Abolishes folate uptake." FT /evidence="ECO:0000269|PubMed:20686069" FT CONFLICT 394 FT /note="A -> G (in Ref. 1; BAB84987)" FT /evidence="ECO:0000305" SQ SEQUENCE 459 AA; 49771 MW; 119F89E9E4ACA5F4 CRC64; MEGSASPPEK PRARPAAAVL CRGPVEPLVF LANFALVLQG PLTTQYLWHR FSADLGYNGT RQRGGCSNRS ADPTMQEVET LTSHWTLYMN VGGFLVGLFS STLLGAWSDS VGRRPLLVLA SLGLLLQALV SVFVVQLQLH VGYFVLGRIL CALLGDFGGL LAASFASVAD VSSSRSRTFR MALLEASIGV AGMLASLLGG HWLRAQGYAN PFWLALALLI AMTLYAAFCF GETLKEPKST RLFTFRHHRS IVQLYVAPAP EKSRKHLALY SLAIFVVITV HFGAQDILTL YELSTPLCWD SKLIGYGSAA QHLPYLTSLL ALKLLQYCLA DAWVAEIGLA FNILGMVVFA FATITPLMFT GYGLLFLSLV ITPVIRAKLS KLVRETEQGA LFSAVACVNS LAMLTASGIF NSLYPATLNF MKGFPFLLGA GLLLIPAVLI GMLEKADPHL EFQQFPQSP //