PCFT_DANRE
ID PCFT_DANRE Reviewed; 481 AA.
AC Q7ZWG6;
DT 08-NOV-2005, integrated into UniProtKB/Swiss-Prot.
DT 01-JUN-2003, sequence version 1.
DT 03-AUG-2022, entry version 86.
DE RecName: Full=Proton-coupled folate transporter {ECO:0000250|UniProtKB:Q96NT5};
DE AltName: Full=Solute carrier family 46 member 1 {ECO:0000305};
GN Name=slc46a1 {ECO:0000250|UniProtKB:Q96NT5};
GN Synonyms=pcft {ECO:0000250|UniProtKB:Q96NT5};
GN ORFNames=zgc:56400 {ECO:0000303|Ref.1};
OS Danio rerio (Zebrafish) (Brachydanio rerio).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Actinopterygii; Neopterygii; Teleostei; Ostariophysi; Cypriniformes;
OC Danionidae; Danioninae; Danio.
OX NCBI_TaxID=7955;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RG NIH - Zebrafish Gene Collection (ZGC) project;
RL Submitted (MAR-2003) to the EMBL/GenBank/DDBJ databases.
CC -!- FUNCTION: Proton-coupled folate symporter that mediates folate
CC absorption using an H(+) gradient as a driving force (By similarity).
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 (By similarity).
CC Functions at acidic pH via alternate outward- and inward-open
CC conformation states (By similarity). Protonation of residues in the
CC outward open state primes the protein for transport (By similarity).
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 (By similarity). Also able
CC to transport antifolate drugs, such as methotrexate and pemetrexed (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). {ECO:0000250|UniProtKB:Q96NT5}.
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:0000250|UniProtKB:Q96NT5};
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 -!- SUBUNIT: Monomer. {ECO:0000250|UniProtKB:F1NJ67}.
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 -!- SIMILARITY: Belongs to the major facilitator superfamily. SLC46A
CC family. {ECO:0000305}.
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DR EMBL; BC049421; AAH49421.1; -; mRNA.
DR RefSeq; NP_956579.1; NM_200285.1.
DR AlphaFoldDB; Q7ZWG6; -.
DR SMR; Q7ZWG6; -.
DR STRING; 7955.ENSDARP00000032054; -.
DR PaxDb; Q7ZWG6; -.
DR GeneID; 393255; -.
DR KEGG; dre:393255; -.
DR CTD; 113235; -.
DR ZFIN; ZDB-GENE-040426-1012; slc46a1.
DR eggNOG; KOG2816; Eukaryota.
DR InParanoid; Q7ZWG6; -.
DR OrthoDB; 763423at2759; -.
DR PhylomeDB; Q7ZWG6; -.
DR Reactome; R-DRE-196757; Metabolism of folate and pterines.
DR Reactome; R-DRE-917937; Iron uptake and transport.
DR Reactome; R-DRE-9707616; Heme signaling.
DR PRO; PR:Q7ZWG6; -.
DR Proteomes; UP000000437; Genome assembly.
DR Proteomes; UP000814640; Unplaced.
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:0015350; F:methotrexate transmembrane transporter activity; ISS:UniProtKB.
DR GO; GO:0015293; F:symporter activity; IEA:UniProtKB-KW.
DR GO; GO:0022857; F:transmembrane transporter activity; IBA:GO_Central.
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 2: Evidence at transcript level;
KW Cell membrane; Cytoplasm; Disulfide bond; Endosome; Folate-binding;
KW Glycoprotein; Membrane; Reference proteome; Symport; Transmembrane;
KW Transmembrane helix; Transport.
FT CHAIN 1..481
FT /note="Proton-coupled folate transporter"
FT /id="PRO_0000084854"
FT TOPO_DOM 1..45
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:F1NJ67"
FT TRANSMEM 46..64
FT /note="Helical; Name=TM1"
FT /evidence="ECO:0000250|UniProtKB:F1NJ67"
FT TOPO_DOM 65..102
FT /note="Extracellular"
FT /evidence="ECO:0000250|UniProtKB:F1NJ67"
FT TRANSMEM 103..128
FT /note="Helical; Name=TM2"
FT /evidence="ECO:0000250|UniProtKB:F1NJ67"
FT TOPO_DOM 129..132
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:F1NJ67"
FT TRANSMEM 133..155
FT /note="Helical; Name=TM3"
FT /evidence="ECO:0000250|UniProtKB:F1NJ67"
FT TOPO_DOM 156..160
FT /note="Extracellular"
FT /evidence="ECO:0000250|UniProtKB:F1NJ67"
FT TRANSMEM 161..174
FT /note="Helical; Name=TM4"
FT /evidence="ECO:0000250|UniProtKB:F1NJ67"
FT TOPO_DOM 175..197
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:F1NJ67"
FT TRANSMEM 198..223
FT /note="Helical; Name=TM5"
FT /evidence="ECO:0000250|UniProtKB:F1NJ67"
FT TOPO_DOM 224..228
FT /note="Extracellular"
FT /evidence="ECO:0000250|UniProtKB:F1NJ67"
FT TRANSMEM 229..247
FT /note="Helical; Name=TM6"
FT /evidence="ECO:0000250|UniProtKB:F1NJ67"
FT TOPO_DOM 248..286
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:F1NJ67"
FT TRANSMEM 287..309
FT /note="Helical; Name=TM7"
FT /evidence="ECO:0000250|UniProtKB:F1NJ67"
FT TOPO_DOM 310..322
FT /note="Extracellular"
FT /evidence="ECO:0000250|UniProtKB:F1NJ67"
FT TRANSMEM 323..345
FT /note="Helical; Name=TM8"
FT /evidence="ECO:0000250|UniProtKB:F1NJ67"
FT TOPO_DOM 346..351
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:F1NJ67"
FT TRANSMEM 352..371
FT /note="Helical; Name=TM9"
FT /evidence="ECO:0000250|UniProtKB:F1NJ67"
FT TOPO_DOM 372..375
FT /note="Extracellular"
FT /evidence="ECO:0000250|UniProtKB:F1NJ67"
FT TRANSMEM 376..396
FT /note="Helical; Name=TM10"
FT /evidence="ECO:0000250|UniProtKB:F1NJ67"
FT TOPO_DOM 397..408
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:F1NJ67"
FT TRANSMEM 409..434
FT /note="Helical; Name=TM11"
FT /evidence="ECO:0000250|UniProtKB:F1NJ67"
FT TOPO_DOM 435..442
FT /note="Extracellular"
FT /evidence="ECO:0000250|UniProtKB:F1NJ67"
FT TRANSMEM 443..461
FT /note="Helical; Name=TM12"
FT /evidence="ECO:0000250|UniProtKB:F1NJ67"
FT TOPO_DOM 462..481
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:F1NJ67"
FT BINDING 176
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 205
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 301
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 CARBOHYD 78
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 86
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 85..318
FT /evidence="ECO:0000250|UniProtKB:F1NJ67"
SQ SEQUENCE 481 AA; 52188 MW; FB408520D6C80C08 CRC64;
MEDSDTSAIL AEDSESVDSR TVCRCFRVTE NKAPPPCSCP LSVTVEPVMF LSTFSIVLQA
PLCTQYLWDR LSEDVGYNGT KTGGCNASTV HDPLQTEVET LTAHWSLYIN LGGFLVGLFM
VILLGSWSDR AGRRLVLIIP SLGLAVQAAV YLTVMYLKLP VFWFLIGRIC SGLSGDFNAI
LAGCFAYVAD TSERGSRTFR VAILEACLGL AGMFASIIGG QWRRAQGYIN PFWLVLATNL
TAALYAYLFV PETVTPDPQA RLFSTRHHQA VCRLYSSDAP PGRRSKLWLY ILCFFLVVTV
HLGCSDLYVL YELSAPLCWG PELIGYGSAA KHLAYLTSLT GLRAMQCCLE DSWVALVGLT
SNMVGLVVIS VADTTALMFT GYGLCFLFMA STPVLRSKLS KLVDPAEQGA LFASVACVEG
LCSLVSSGVF NALYPATLHF MKGFPFVFGA AILLIPAGII GGLGCQEKRE SRENREGFGI
S
