PCFT_RAT
ID PCFT_RAT Reviewed; 459 AA.
AC Q5EBA8;
DT 08-NOV-2005, integrated into UniProtKB/Swiss-Prot.
DT 15-MAR-2005, sequence version 1.
DT 03-AUG-2022, entry version 114.
DE RecName: Full=Proton-coupled folate transporter {ECO:0000303|PubMed:31792273};
DE Short=rPCFT {ECO:0000303|PubMed:31792273};
DE AltName: Full=Heme carrier protein 1 {ECO:0000303|PubMed:16143108};
DE AltName: Full=PCFT/HCP1 {ECO:0000303|PubMed:18174275};
DE AltName: Full=Solute carrier family 46 member 1 {ECO:0000305};
GN Name=Slc46a1 {ECO:0000312|RGD:1309472};
GN Synonyms=Hcp1 {ECO:0000303|PubMed:16143108},
GN Pcft {ECO:0000303|PubMed:31792273};
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Liver;
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 [2]
RP TISSUE SPECIFICITY.
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 [3]
RP FUNCTION, TRANSPORTER ACTIVITY, AND BIOPHYSICOCHEMICAL PROPERTIES.
RX PubMed=18174275; DOI=10.1152/ajpgi.00309.2007;
RA Inoue K., Nakai Y., Ueda S., Kamigaso S., Ohta K.Y., Hatakeyama M.,
RA Hayashi Y., Otagiri M., Yuasa H.;
RT "Functional characterization of PCFT/HCP1 as the molecular entity of the
RT carrier-mediated intestinal folate transport system in the rat model.";
RL Am. J. Physiol. 294:G660-G668(2008).
RN [4]
RP FUNCTION, ACTIVITY REGULATION, AND MUTAGENESIS OF ASN-158.
RX PubMed=31792273; DOI=10.1038/s41598-019-54367-9;
RA Yamashiro T., Yasujima T., Ohta K., Inoue K., Yuasa H.;
RT "Identification of the amino acid residue responsible for the myricetin
RT sensitivity of human proton-coupled folate transporter.";
RL Sci. Rep. 9:18105-18105(2019).
CC -!- FUNCTION: Proton-coupled folate symporter that mediates folate
CC absorption using an H(+) gradient as a driving force (PubMed:18174275,
CC PubMed:31792273). Involved in the intestinal absorption of folates at
CC the brush-border membrane of the proximal jejunum, and the transport
CC from blood to cerebrospinal fluid across the choroid plexus
CC (PubMed:18174275). Functions at acidic pH via alternate outward- and
CC inward-open conformation states (By similarity). Protonation of
CC residues in the outward open state primes the protein for transport (By
CC similarity). Binding of folate promotes breaking of salt bridge network
CC and subsequent closure of the extracellular gate, leading to the
CC inward-open state and release of protons and folate (By similarity).
CC Also able to transport antifolate drugs, such as methotrexate and
CC pemetrexed (PubMed:18174275). Involved in FOLR1-mediated endocytosis by
CC serving as a route of export of folates from acidified endosomes (By
CC similarity). Also acts as a lower-affinity, pH-independent heme carrier
CC protein and constitutes the main importer of heme in the intestine (By
CC similarity). Imports heme in the retina and retinal pigment epithelium,
CC in neurons of the hippocampus, in hepatocytes and in the renal
CC epithelial cells (By similarity). Hence, participates in the
CC trafficking of heme and increases intracellular iron content (By
CC similarity). {ECO:0000250|UniProtKB:Q96NT5,
CC ECO:0000269|PubMed:18174275, ECO:0000269|PubMed:31792273}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=folate(in) + H(+)(in) = folate(out) + H(+)(out);
CC Xref=Rhea:RHEA:70159, ChEBI:CHEBI:15378, ChEBI:CHEBI:62501;
CC Evidence={ECO:0000305|PubMed:18174275};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(6S)-5-methyl-5,6,7,8-tetrahydrofolate(in) + H(+)(in) = (6S)-
CC 5-methyl-5,6,7,8-tetrahydrofolate(out) + H(+)(out);
CC Xref=Rhea:RHEA:70167, ChEBI:CHEBI:15378, ChEBI:CHEBI:18608;
CC Evidence={ECO:0000250|UniProtKB:Q6PEM8};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H(+)(in) + methotrexate(in) = H(+)(out) + methotrexate(out);
CC Xref=Rhea:RHEA:70163, ChEBI:CHEBI:15378, ChEBI:CHEBI:50681;
CC Evidence={ECO:0000305|PubMed:18174275};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H(+)(in) + pemetrexed(in) = H(+)(out) + pemetrexed(out);
CC Xref=Rhea:RHEA:70171, ChEBI:CHEBI:15378, ChEBI:CHEBI:63724;
CC Evidence={ECO:0000250|UniProtKB:Q96NT5};
CC -!- ACTIVITY REGULATION: In contrast to human ortholog, not inhibited by
CC myricetin. {ECO:0000269|PubMed:31792273}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=2.4 uM for folic acid {ECO:0000269|PubMed:18174275};
CC KM=5.7 uM for methotrexate {ECO:0000269|PubMed:18174275};
CC pH dependence:
CC Optimum pH is 5.5. {ECO:0000269|PubMed:18174275};
CC -!- SUBUNIT: Monomer. {ECO:0000250|UniProtKB:Q96NT5}.
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000250|UniProtKB:Q96NT5};
CC Multi-pass membrane protein {ECO:0000255}. Apical cell membrane
CC {ECO:0000250|UniProtKB:Q96NT5}; Multi-pass membrane protein
CC {ECO:0000255}. Basolateral cell membrane
CC {ECO:0000250|UniProtKB:Q96NT5}; Multi-pass membrane protein
CC {ECO:0000255}. Endosome membrane {ECO:0000250|UniProtKB:Q96NT5}; Multi-
CC pass membrane protein {ECO:0000255}. Cytoplasm
CC {ECO:0000250|UniProtKB:Q6PEM8}. 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 (By similarity). Localizes to the
CC basolateral membrane of choroid plexus (By similarity).
CC {ECO:0000250|UniProtKB:Q6PEM8}.
CC -!- TISSUE SPECIFICITY: Expressed almost exclusively in the small
CC intestine: expressed at high level in the upper half of the small
CC intestine (duodenum and jejunum), expression decreases downwardly in
CC the subsequent quarter and is undetectable in the last quarter (the
CC lowest ileum) (PubMed:18174275). Expressed at low level in other
CC tissues, including liver (PubMed:16143108, PubMed:18174275).
CC {ECO:0000269|PubMed:16143108, ECO:0000269|PubMed:18174275}.
CC -!- SIMILARITY: Belongs to the major facilitator superfamily. SLC46A
CC family. {ECO:0000305}.
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DR EMBL; BC089868; AAH89868.1; -; mRNA.
DR RefSeq; NP_001013991.1; NM_001013969.1.
DR RefSeq; XP_006247001.1; XM_006246939.3.
DR AlphaFoldDB; Q5EBA8; -.
DR SMR; Q5EBA8; -.
DR STRING; 10116.ENSRNOP00000013698; -.
DR GlyGen; Q5EBA8; 2 sites.
DR iPTMnet; Q5EBA8; -.
DR PhosphoSitePlus; Q5EBA8; -.
DR PaxDb; Q5EBA8; -.
DR Ensembl; ENSRNOT00000013698; ENSRNOP00000013698; ENSRNOG00000010291.
DR GeneID; 303333; -.
DR KEGG; rno:303333; -.
DR CTD; 113235; -.
DR RGD; 1309472; Slc46a1.
DR eggNOG; KOG2816; Eukaryota.
DR GeneTree; ENSGT00950000183096; -.
DR HOGENOM; CLU_028365_1_0_1; -.
DR InParanoid; Q5EBA8; -.
DR OMA; SPRANDE; -.
DR OrthoDB; 763423at2759; -.
DR PhylomeDB; Q5EBA8; -.
DR TreeFam; TF315701; -.
DR Reactome; R-RNO-196757; Metabolism of folate and pterines.
DR Reactome; R-RNO-917937; Iron uptake and transport.
DR Reactome; R-RNO-9707616; Heme signaling.
DR PRO; PR:Q5EBA8; -.
DR Proteomes; UP000002494; Chromosome 10.
DR Bgee; ENSRNOG00000010291; Expressed in liver and 18 other tissues.
DR Genevisible; Q5EBA8; RN.
DR GO; GO:0016324; C:apical plasma membrane; ISS:UniProtKB.
DR GO; GO:0016323; C:basolateral plasma membrane; ISS:UniProtKB.
DR GO; GO:0031526; C:brush border membrane; IDA:RGD.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0005768; C:endosome; ISS:UniProtKB.
DR GO; GO:0010008; C:endosome membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0016020; C:membrane; IBA:GO_Central.
DR GO; GO:0005886; C:plasma membrane; ISO:RGD.
DR GO; GO:0005542; F:folic acid binding; IEA:UniProtKB-KW.
DR GO; GO:0008517; F:folic acid transmembrane transporter activity; IDA:RGD.
DR GO; GO:0140211; F:folic acid:proton symporter activity; ISO:RGD.
DR GO; GO:0015232; F:heme transmembrane transporter activity; ISS:UniProtKB.
DR GO; GO:0015350; F:methotrexate transmembrane transporter activity; ISS:UniProtKB.
DR GO; GO:0015078; F:proton transmembrane transporter activity; ISO:RGD.
DR GO; GO:0022857; F:transmembrane transporter activity; IBA:GO_Central.
DR GO; GO:1904447; P:folate import across plasma membrane; ISO:RGD.
DR GO; GO:0098838; P:folate transmembrane transport; ISO:RGD.
DR GO; GO:0015884; P:folic acid transport; IDA:RGD.
DR GO; GO:0015886; P:heme transport; ISS:UniProtKB.
DR GO; GO:1902600; P:proton transmembrane transport; ISO:RGD.
DR GO; GO:0055085; P:transmembrane transport; IBA:GO_Central.
DR Gene3D; 1.20.1250.20; -; 1.
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; Cell membrane; Cytoplasm; Disulfide bond; Endosome;
KW Folate-binding; Glycoprotein; Membrane; Phosphoprotein; Reference proteome;
KW Symport; Transmembrane; Transmembrane helix; Transport.
FT CHAIN 1..459
FT /note="Proton-coupled folate transporter"
FT /id="PRO_0000084853"
FT TOPO_DOM 1..25
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:F1NJ67"
FT TRANSMEM 26..44
FT /note="Helical; Name=TM1"
FT /evidence="ECO:0000250|UniProtKB:F1NJ67"
FT TOPO_DOM 45..82
FT /note="Extracellular"
FT /evidence="ECO:0000250|UniProtKB:F1NJ67"
FT TRANSMEM 83..108
FT /note="Helical; Name=TM2"
FT /evidence="ECO:0000250|UniProtKB:F1NJ67"
FT TOPO_DOM 109..112
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:F1NJ67"
FT TRANSMEM 113..135
FT /note="Helical; Name=TM3"
FT /evidence="ECO:0000250|UniProtKB:F1NJ67"
FT TOPO_DOM 136..140
FT /note="Extracellular"
FT /evidence="ECO:0000250|UniProtKB:F1NJ67"
FT TRANSMEM 141..154
FT /note="Helical; Name=TM4"
FT /evidence="ECO:0000250|UniProtKB:F1NJ67"
FT TOPO_DOM 155..177
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:F1NJ67"
FT TRANSMEM 178..203
FT /note="Helical; Name=TM5"
FT /evidence="ECO:0000250|UniProtKB:F1NJ67"
FT TOPO_DOM 204..208
FT /note="Extracellular"
FT /evidence="ECO:0000250|UniProtKB:F1NJ67"
FT TRANSMEM 209..227
FT /note="Helical; Name=TM6"
FT /evidence="ECO:0000250|UniProtKB:F1NJ67"
FT TOPO_DOM 228..266
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:F1NJ67"
FT TRANSMEM 267..289
FT /note="Helical; Name=TM7"
FT /evidence="ECO:0000250|UniProtKB:F1NJ67"
FT TOPO_DOM 290..302
FT /note="Extracellular"
FT /evidence="ECO:0000250|UniProtKB:F1NJ67"
FT TRANSMEM 303..325
FT /note="Helical; Name=TM8"
FT /evidence="ECO:0000250|UniProtKB:F1NJ67"
FT TOPO_DOM 326..331
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:F1NJ67"
FT TRANSMEM 332..351
FT /note="Helical; Name=TM9"
FT /evidence="ECO:0000250|UniProtKB:F1NJ67"
FT TOPO_DOM 352..355
FT /note="Extracellular"
FT /evidence="ECO:0000250|UniProtKB:F1NJ67"
FT TRANSMEM 356..376
FT /note="Helical; Name=TM10"
FT /evidence="ECO:0000250|UniProtKB:F1NJ67"
FT TOPO_DOM 377..388
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:F1NJ67"
FT TRANSMEM 389..414
FT /note="Helical; Name=TM11"
FT /evidence="ECO:0000250|UniProtKB:F1NJ67"
FT TOPO_DOM 415..422
FT /note="Extracellular"
FT /evidence="ECO:0000250|UniProtKB:F1NJ67"
FT TRANSMEM 423..441
FT /note="Helical; Name=TM12"
FT /evidence="ECO:0000250|UniProtKB:F1NJ67"
FT TOPO_DOM 442..459
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:F1NJ67"
FT BINDING 156
FT /ligand="H(+)"
FT /ligand_id="ChEBI:CHEBI:15378"
FT /note="reversibly protonated residue during proton
FT transport"
FT /evidence="ECO:0000250|UniProtKB:Q96NT5"
FT BINDING 185
FT /ligand="H(+)"
FT /ligand_id="ChEBI:CHEBI:15378"
FT /note="reversibly protonated residue during proton
FT transport"
FT /evidence="ECO:0000250|UniProtKB:Q96NT5"
FT BINDING 281
FT /ligand="H(+)"
FT /ligand_id="ChEBI:CHEBI:15378"
FT /note="reversibly protonated residue during proton
FT transport"
FT /evidence="ECO:0000250|UniProtKB:Q96NT5"
FT MOD_RES 1
FT /note="N-acetylmethionine"
FT /evidence="ECO:0000250|UniProtKB:Q96NT5"
FT MOD_RES 6
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q96NT5"
FT CARBOHYD 58
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 68
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 66..298
FT /evidence="ECO:0000250|UniProtKB:F1NJ67"
FT MUTAGEN 158
FT /note="N->G: Promotes sensitivity to myricetin inhibitor."
FT /evidence="ECO:0000269|PubMed:31792273"
SQ SEQUENCE 459 AA; 50095 MW; 4F590DA8DE7D6FA7 CRC64;
MEGRVSPVGS SHRLLTAAVL FRGPVEPLVF LANFALVLQG PLTTQYIWHR ISTELGYNGT
RHRENCGNQS ADPVLKEVET LTSHWTLYMN VGGFLVGLFW STLLGAWSDR VGRRPLLVLA
SLGLLLQAVV SIFVVQLQLH IGFFVLGRAL CALLGDFNGL LAASFASVAD VSSNHSRTFR
MALLEACIGV AGTLASLLGG HWLRAQGYAN PFWLALAVLI VMTLYAAFCF GETVKEPKST
RLFTLRHHRS IVQLYVVPAP EKSRMHLALY SLAIFVVVTV HFGAQDILTL YELSTPLCWD
SKLIGYGSAA QHLPYLTSLL GLRLLQFCLA DTWVAEIGLA FNILGMVVFA FATITPLMFT
GYGLLFLSLV TTPVIRAKLS KLVSESEQGA LFSAVACVNS LAMLMASGIF NSLYPATLNF
MKGFPFLLGA GLLFIPAILI GVLEKVNPHP EFQQFPQNS
