PCFT_CHICK
ID PCFT_CHICK Reviewed; 473 AA.
AC F1NJ67; E6Y8U5;
DT 25-MAY-2022, integrated into UniProtKB/Swiss-Prot.
DT 26-JUN-2013, sequence version 2.
DT 03-AUG-2022, entry version 60.
DE RecName: Full=Proton-coupled folate transporter {ECO:0000303|PubMed:21058067};
DE AltName: Full=Solute carrier family 46 member 1 {ECO:0000305};
GN Name=SLC46A1 {ECO:0000250|UniProtKB:Q96NT5};
GN Synonyms=PCFT {ECO:0000303|PubMed:21058067};
OS Gallus gallus (Chicken).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Archelosauria; Archosauria; Dinosauria; Saurischia; Theropoda;
OC Coelurosauria; Aves; Neognathae; Galloanserae; Galliformes; Phasianidae;
OC Phasianinae; Gallus.
OX NCBI_TaxID=9031;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND TISSUE SPECIFICITY.
RX PubMed=21058067; DOI=10.1080/00071668.2010.508490;
RA Jing M., Tactacan G.B., Rodriguez-Lecompte J.C., Kroeker A., House J.D.;
RT "Proton-coupled folate transporter (PCFT): molecular cloning, tissue
RT expression patterns and the effects of dietary folate supplementation on
RT mRNA expression in laying hens.";
RL Br. Poult. Sci. 51:635-638(2010).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=Red jungle fowl;
RX PubMed=15592404; DOI=10.1038/nature03154;
RA Hillier L.W., Miller W., Birney E., Warren W., Hardison R.C., Ponting C.P.,
RA Bork P., Burt D.W., Groenen M.A.M., Delany M.E., Dodgson J.B.,
RA Chinwalla A.T., Cliften P.F., Clifton S.W., Delehaunty K.D., Fronick C.,
RA Fulton R.S., Graves T.A., Kremitzki C., Layman D., Magrini V.,
RA McPherson J.D., Miner T.L., Minx P., Nash W.E., Nhan M.N., Nelson J.O.,
RA Oddy L.G., Pohl C.S., Randall-Maher J., Smith S.M., Wallis J.W.,
RA Yang S.-P., Romanov M.N., Rondelli C.M., Paton B., Smith J., Morrice D.,
RA Daniels L., Tempest H.G., Robertson L., Masabanda J.S., Griffin D.K.,
RA Vignal A., Fillon V., Jacobbson L., Kerje S., Andersson L.,
RA Crooijmans R.P., Aerts J., van der Poel J.J., Ellegren H., Caldwell R.B.,
RA Hubbard S.J., Grafham D.V., Kierzek A.M., McLaren S.R., Overton I.M.,
RA Arakawa H., Beattie K.J., Bezzubov Y., Boardman P.E., Bonfield J.K.,
RA Croning M.D.R., Davies R.M., Francis M.D., Humphray S.J., Scott C.E.,
RA Taylor R.G., Tickle C., Brown W.R.A., Rogers J., Buerstedde J.-M.,
RA Wilson S.A., Stubbs L., Ovcharenko I., Gordon L., Lucas S., Miller M.M.,
RA Inoko H., Shiina T., Kaufman J., Salomonsen J., Skjoedt K., Wong G.K.-S.,
RA Wang J., Liu B., Wang J., Yu J., Yang H., Nefedov M., Koriabine M.,
RA Dejong P.J., Goodstadt L., Webber C., Dickens N.J., Letunic I., Suyama M.,
RA Torrents D., von Mering C., Zdobnov E.M., Makova K., Nekrutenko A.,
RA Elnitski L., Eswara P., King D.C., Yang S.-P., Tyekucheva S.,
RA Radakrishnan A., Harris R.S., Chiaromonte F., Taylor J., He J.,
RA Rijnkels M., Griffiths-Jones S., Ureta-Vidal A., Hoffman M.M., Severin J.,
RA Searle S.M.J., Law A.S., Speed D., Waddington D., Cheng Z., Tuzun E.,
RA Eichler E., Bao Z., Flicek P., Shteynberg D.D., Brent M.R., Bye J.M.,
RA Huckle E.J., Chatterji S., Dewey C., Pachter L., Kouranov A.,
RA Mourelatos Z., Hatzigeorgiou A.G., Paterson A.H., Ivarie R., Brandstrom M.,
RA Axelsson E., Backstrom N., Berlin S., Webster M.T., Pourquie O.,
RA Reymond A., Ucla C., Antonarakis S.E., Long M., Emerson J.J., Betran E.,
RA Dupanloup I., Kaessmann H., Hinrichs A.S., Bejerano G., Furey T.S.,
RA Harte R.A., Raney B., Siepel A., Kent W.J., Haussler D., Eyras E.,
RA Castelo R., Abril J.F., Castellano S., Camara F., Parra G., Guigo R.,
RA Bourque G., Tesler G., Pevzner P.A., Smit A., Fulton L.A., Mardis E.R.,
RA Wilson R.K.;
RT "Sequence and comparative analysis of the chicken genome provide unique
RT perspectives on vertebrate evolution.";
RL Nature 432:695-716(2004).
RN [3] {ECO:0007744|PDB:7BC6, ECO:0007744|PDB:7BC7}
RP STRUCTURE BY ELECTRON MICROSCOPY (3.20 ANGSTROMS), DISULFIDE BONDS,
RP FUNCTION, TRANSPORTER ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, SUBUNIT, AND
RP MUTAGENESIS OF ASP-164 AND GLU-193.
RX PubMed=34040256; DOI=10.1038/s41586-021-03579-z;
RA Parker J.L., Deme J.C., Kuteyi G., Wu Z., Huo J., Goldman I.D., Owens R.J.,
RA Biggin P.C., Lea S.M., Newstead S.;
RT "Structural basis of antifolate recognition and transport by PCFT.";
RL Nature 595:130-134(2021).
CC -!- FUNCTION: Proton-coupled folate symporter that mediates folate
CC absorption using an H(+) gradient as a driving force (PubMed:34040256).
CC Involved in the intestinal absorption of folates at the brush-border
CC membrane of the proximal jejunum, and the transport from blood to
CC cerebrospinal fluid across the choroid plexus (PubMed:34040256).
CC Functions at acidic pH via alternate outward- and inward-open
CC conformation states (PubMed:34040256). Protonation of residues in the
CC outward open state primes the protein for transport (PubMed:34040256).
CC Binding of folate promotes breaking of salt bridge network and
CC subsequent closure of the extracellular gate, leading to the inward-
CC open state and release of protons and folate (PubMed:34040256). Also
CC able to transport antifolate drugs, such as methotrexate and pemetrexed
CC (PubMed:34040256). Also acts as a lower-affinity, pH-independent heme
CC carrier protein and constitutes the main importer of heme in the
CC intestine (By similarity). Imports heme in the retina and retinal
CC pigment epithelium, in neurons of the hippocampus, in hepatocytes and
CC in the renal epithelial cells (By similarity).
CC {ECO:0000250|UniProtKB:Q96NT5, ECO:0000269|PubMed:34040256}.
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:34040256};
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:0000250|UniProtKB:Q96NT5};
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 -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=2 uM for folic acid {ECO:0000269|PubMed:34040256};
CC pH dependence:
CC Optimum pH is 5.0-5.5. {ECO:0000269|PubMed:34040256};
CC -!- SUBUNIT: Monomer. {ECO:0000269|PubMed:34040256}.
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000250|UniProtKB:Q96NT5};
CC Multi-pass membrane protein {ECO:0000269|PubMed:34040256}. Apical cell
CC membrane {ECO:0000250|UniProtKB:Q96NT5}; Multi-pass membrane protein
CC {ECO:0000269|PubMed:34040256}. 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: Widely expressed, including brain, aorta, liver,
CC kidney, spleen, small intestine, pancreas, ovary and testis.
CC {ECO:0000269|PubMed:21058067}.
CC -!- SIMILARITY: Belongs to the major facilitator superfamily. SLC46A
CC family. {ECO:0000305}.
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DR EMBL; FJ655775; ACV70072.1; -; mRNA.
DR EMBL; AADN05000057; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR RefSeq; NP_001191995.1; NM_001205066.1.
DR PDB; 7BC6; EM; 3.20 A; A=1-473.
DR PDB; 7BC7; EM; 3.30 A; A=1-473.
DR PDBsum; 7BC6; -.
DR PDBsum; 7BC7; -.
DR STRING; 9031.ENSGALP00000005695; -.
DR PaxDb; F1NJ67; -.
DR Ensembl; ENSGALT00000005705; ENSGALP00000005695; ENSGALG00000003604.
DR GeneID; 417569; -.
DR KEGG; gga:417569; -.
DR CTD; 113235; -.
DR VEuPathDB; HostDB:geneid_417569; -.
DR eggNOG; KOG2816; Eukaryota.
DR GeneTree; ENSGT00950000183096; -.
DR HOGENOM; CLU_028365_1_1_1; -.
DR InParanoid; F1NJ67; -.
DR OMA; SPRANDE; -.
DR OrthoDB; 763423at2759; -.
DR TreeFam; TF315701; -.
DR Reactome; R-GGA-196757; Metabolism of folate and pterines.
DR Reactome; R-GGA-917937; Iron uptake and transport.
DR Reactome; R-GGA-9707616; Heme signaling.
DR Proteomes; UP000000539; Chromosome 19.
DR Bgee; ENSGALG00000003604; Expressed in kidney and 12 other tissues.
DR GO; GO:0016324; C:apical plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0016323; C:basolateral plasma membrane; 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; IBA:GO_Central.
DR GO; GO:0005542; F:folic acid binding; IEA:UniProtKB-KW.
DR GO; GO:0140211; F:folic acid:proton symporter activity; IDA:UniProtKB.
DR GO; GO:0015350; F:methotrexate transmembrane transporter activity; ISS:UniProtKB.
DR GO; GO:0022857; F:transmembrane transporter activity; IBA:GO_Central.
DR GO; GO:1904447; P:folate import across plasma membrane; IDA:UniProtKB.
DR GO; GO:0055085; P:transmembrane transport; IBA:GO_Central.
DR Gene3D; 1.20.1250.20; -; 1.
DR InterPro; IPR011701; MFS.
DR InterPro; IPR036259; MFS_trans_sf.
DR Pfam; PF07690; MFS_1; 1.
DR SUPFAM; SSF103473; SSF103473; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Cell membrane; Cytoplasm; Disulfide bond; Endosome;
KW Folate-binding; Glycoprotein; Membrane; Reference proteome; Symport;
KW Transmembrane; Transmembrane helix; Transport.
FT CHAIN 1..473
FT /note="Proton-coupled folate transporter"
FT /id="PRO_0000455380"
FT TOPO_DOM 1..29
FT /note="Cytoplasmic"
FT /evidence="ECO:0000269|PubMed:34040256,
FT ECO:0007744|PDB:7BC6, ECO:0007744|PDB:7BC7"
FT TRANSMEM 30..48
FT /note="Helical; Name=TM1"
FT /evidence="ECO:0000269|PubMed:34040256,
FT ECO:0007744|PDB:7BC6, ECO:0007744|PDB:7BC7"
FT TOPO_DOM 49..90
FT /note="Extracellular"
FT /evidence="ECO:0000269|PubMed:34040256,
FT ECO:0007744|PDB:7BC6, ECO:0007744|PDB:7BC7"
FT TRANSMEM 91..116
FT /note="Helical; Name=TM2"
FT /evidence="ECO:0000269|PubMed:34040256,
FT ECO:0007744|PDB:7BC6, ECO:0007744|PDB:7BC7"
FT TOPO_DOM 117..120
FT /note="Cytoplasmic"
FT /evidence="ECO:0000269|PubMed:34040256,
FT ECO:0007744|PDB:7BC6, ECO:0007744|PDB:7BC7"
FT TRANSMEM 121..143
FT /note="Helical; Name=TM3"
FT /evidence="ECO:0000269|PubMed:34040256,
FT ECO:0007744|PDB:7BC6, ECO:0007744|PDB:7BC7"
FT TOPO_DOM 144..148
FT /note="Extracellular"
FT /evidence="ECO:0000269|PubMed:34040256,
FT ECO:0007744|PDB:7BC6, ECO:0007744|PDB:7BC7"
FT TRANSMEM 149..162
FT /note="Helical; Name=TM4"
FT /evidence="ECO:0000269|PubMed:34040256,
FT ECO:0007744|PDB:7BC6, ECO:0007744|PDB:7BC7"
FT TOPO_DOM 163..185
FT /note="Cytoplasmic"
FT /evidence="ECO:0000269|PubMed:34040256,
FT ECO:0007744|PDB:7BC6, ECO:0007744|PDB:7BC7"
FT TRANSMEM 186..211
FT /note="Helical; Name=TM5"
FT /evidence="ECO:0000269|PubMed:34040256,
FT ECO:0007744|PDB:7BC6, ECO:0007744|PDB:7BC7"
FT TOPO_DOM 212..216
FT /note="Extracellular"
FT /evidence="ECO:0000269|PubMed:34040256,
FT ECO:0007744|PDB:7BC6, ECO:0007744|PDB:7BC7"
FT TRANSMEM 217..235
FT /note="Helical; Name=TM6"
FT /evidence="ECO:0000269|PubMed:34040256,
FT ECO:0007744|PDB:7BC6, ECO:0007744|PDB:7BC7"
FT TOPO_DOM 236..274
FT /note="Cytoplasmic"
FT /evidence="ECO:0000269|PubMed:34040256,
FT ECO:0007744|PDB:7BC6, ECO:0007744|PDB:7BC7"
FT TRANSMEM 275..297
FT /note="Helical; Name=TM7"
FT /evidence="ECO:0000269|PubMed:34040256,
FT ECO:0007744|PDB:7BC6, ECO:0007744|PDB:7BC7"
FT TOPO_DOM 298..310
FT /note="Extracellular"
FT /evidence="ECO:0000269|PubMed:34040256,
FT ECO:0007744|PDB:7BC6, ECO:0007744|PDB:7BC7"
FT TRANSMEM 311..333
FT /note="Helical; Name=TM8"
FT /evidence="ECO:0000269|PubMed:34040256,
FT ECO:0007744|PDB:7BC6, ECO:0007744|PDB:7BC7"
FT TOPO_DOM 334..339
FT /note="Cytoplasmic"
FT /evidence="ECO:0000269|PubMed:34040256,
FT ECO:0007744|PDB:7BC6, ECO:0007744|PDB:7BC7"
FT TRANSMEM 340..359
FT /note="Helical; Name=TM9"
FT /evidence="ECO:0000269|PubMed:34040256,
FT ECO:0007744|PDB:7BC6, ECO:0007744|PDB:7BC7"
FT TOPO_DOM 360..363
FT /note="Extracellular"
FT /evidence="ECO:0000269|PubMed:34040256,
FT ECO:0007744|PDB:7BC6, ECO:0007744|PDB:7BC7"
FT TRANSMEM 364..384
FT /note="Helical; Name=TM10"
FT /evidence="ECO:0000269|PubMed:34040256,
FT ECO:0007744|PDB:7BC6, ECO:0007744|PDB:7BC7"
FT TOPO_DOM 385..396
FT /note="Cytoplasmic"
FT /evidence="ECO:0000269|PubMed:34040256,
FT ECO:0007744|PDB:7BC6, ECO:0007744|PDB:7BC7"
FT TRANSMEM 397..422
FT /note="Helical; Name=TM11"
FT /evidence="ECO:0000269|PubMed:34040256,
FT ECO:0007744|PDB:7BC6, ECO:0007744|PDB:7BC7"
FT TOPO_DOM 423..430
FT /note="Extracellular"
FT /evidence="ECO:0000269|PubMed:34040256,
FT ECO:0007744|PDB:7BC6, ECO:0007744|PDB:7BC7"
FT TRANSMEM 431..449
FT /note="Helical; Name=TM12"
FT /evidence="ECO:0000269|PubMed:34040256,
FT ECO:0007744|PDB:7BC6, ECO:0007744|PDB:7BC7"
FT TOPO_DOM 450..473
FT /note="Cytoplasmic"
FT /evidence="ECO:0000269|PubMed:34040256,
FT ECO:0007744|PDB:7BC6, ECO:0007744|PDB:7BC7"
FT REGION 1..21
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 98
FT /ligand="pemetrexed"
FT /ligand_id="ChEBI:CHEBI:63724"
FT /evidence="ECO:0000269|PubMed:34040256,
FT ECO:0007744|PDB:7BC7"
FT BINDING 164
FT /ligand="H(+)"
FT /ligand_id="ChEBI:CHEBI:15378"
FT /note="reversibly protonated residue during proton
FT transport"
FT /evidence="ECO:0000269|PubMed:34040256"
FT BINDING 193
FT /ligand="H(+)"
FT /ligand_id="ChEBI:CHEBI:15378"
FT /note="reversibly protonated residue during proton
FT transport"
FT /evidence="ECO:0000269|PubMed:34040256"
FT BINDING 193
FT /ligand="pemetrexed"
FT /ligand_id="ChEBI:CHEBI:63724"
FT /evidence="ECO:0000269|PubMed:34040256,
FT ECO:0007744|PDB:7BC7"
FT BINDING 289
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 323
FT /ligand="pemetrexed"
FT /ligand_id="ChEBI:CHEBI:63724"
FT /evidence="ECO:0000269|PubMed:34040256,
FT ECO:0007744|PDB:7BC7"
FT BINDING 407
FT /ligand="pemetrexed"
FT /ligand_id="ChEBI:CHEBI:63724"
FT /evidence="ECO:0000269|PubMed:34040256,
FT ECO:0007744|PDB:7BC7"
FT BINDING 411
FT /ligand="pemetrexed"
FT /ligand_id="ChEBI:CHEBI:63724"
FT /evidence="ECO:0000269|PubMed:34040256,
FT ECO:0007744|PDB:7BC7"
FT CARBOHYD 65
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 74
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT DISULFID 72..306
FT /evidence="ECO:0000269|PubMed:34040256,
FT ECO:0007744|PDB:7BC6, ECO:0007744|PDB:7BC7"
FT MUTAGEN 164
FT /note="D->N: Strongly reduced proton-coupled folate
FT transport."
FT /evidence="ECO:0000269|PubMed:34040256"
FT MUTAGEN 193
FT /note="E->A: Abolished proton-coupled folate transport."
FT /evidence="ECO:0000269|PubMed:34040256"
FT MUTAGEN 193
FT /note="E->N: Strong proton-coupled folate transport at pH
FT 7.5."
FT /evidence="ECO:0000269|PubMed:34040256"
FT CONFLICT 25
FT /note="L -> P (in Ref. 1; ACV70072)"
FT /evidence="ECO:0000305"
FT CONFLICT 392
FT /note="G -> S (in Ref. 1; ACV70072)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 473 AA; 50465 MW; 794BE71E3B571BEA CRC64;
MAAPSDPPTA ATPPAPPPPA RRCLLAPSVE PLLFLATLAL GLQVPLATQY LWDRLGAERG
YVGPNASSPH GCGNGSGAVD PLREEVEALV AHWNLCINLG GFFVGLFSVT LFGPWSDSVG
RRPVLVLPAV GMAVQAAVYL LVMYLRLHVA YLLLGRIISG LLGDYNLILA GCFASVADSS
NQRTRTFRVA ILEACLGVAG MVASVGGGQW RKAEGYINPF WLVLAASLAA ALYAALCLQE
TVKQRRAAKL LTLQHYKAVY KLYTAPEDLS SRRKLALYSL AFFLLVTVHF GTKDLYVLYE
LGSPLCWASD LIGYGSAASY LAYLSSLGGL RLLQLCLEDT WVAEIGLISN IAGLVVISLA
TTTPLMFTGY GIMFLSMAAT PVIRAKLSKL VGETEQGALF ASVACVEGLC SLVATGVFNS
LYPSTLHFMR GFPFLFGAIL LLIPAAIMGW IEIQDSNLQY SHFSDASSSP ADG
