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2.A.1.50.1
The apical intestinal and choroid plexus proton-coupled, high affinity folate transporter, the hereditary folate malabsorption protein, PCFT/HCP1 (Shin et al. 2010).  Also reported to mediate heme-iron uptake from the gut lumen with duodenal epithelial cells (Shayeghi et al., 2005; Latunde-Dada et al., 2006; Subramanian et al., 2008, Shin et al., 2012b), but it shows a higher affinity for folate than heme) (Qiu et al., 2006). Responsible for folate uptake by choroid plexus epithelial cells (Wollack et al., 2007) and placenta (Yasuda et al., 2008). The rat orthologue (Q5EBA8) catalyzes H+-dependent folate uptake in the intestine (Inoue et al., 2008). Responsible for the rare autosomal recessive disorder, hereditary folate malabsorption (Zhao and Goldman, 2007). PCFT/ICP1, when mutated, is the cause of Hereditary Folate Malabsorption in humans (Qiu et al., 2006; Shin et al., 2012). Evidence for a 12 TMS topology with a renetrant look between TMSs 2 and 3 has been presented (Zhao et al., 2010; Qiu et al., 2006; Zhao et al., 2011; Wilson et al. 2014).  Downregulated in Chronic Kidney Disease (CKD) in heart, liver, and brain causing malabsorption (Bukhari et al., 2011). An IGXXG motif in TMS5 is important for folate binding and a GXXXG motif is involved in dimerization (Zhao et al., 2012). Inhibited by bicarbonate, bisulfite, nitrite and other anions (Zhao et al. 2013).  Its role in antifolate cancer chemotherapy has been reviewed (Matherly et al. 2014). TMSs 3 and 6 may provide critical interfaces for formation of hPCFT oligomers, facilitated by the GXXXG motifs in TMS2 and TMS4 (Wilson et al. 2015).  The extracellular gate has been identified (Zhao et al. 2016), and mechanistic aspects have been considered (Date et al. 2016). Residues in the eighth TMS play roles in the translocation pathway and folate binding (Aluri et al. 2017).

Accession Number:Q96NT5
Protein Name:Proton-coupled folate transporter aka HCP4
Length:459
Molecular Weight:49771.00
Species:Homo sapiens (human) [9606]
Number of TMSs:12
Location1 / Topology2 / Orientation3: Apical cell membrane1 / Multi-pass membrane protein2
Substrate folate

Cross database links:

Genevestigator: Q96NT5 Q96NT5
eggNOG: prNOG19006 NOG306680
HEGENOM: HBG712992 HOG000054191
RefSeq: NP_542400.2   
Entrez Gene ID: 113235   
Pfam: PF07690   
OMIM: 229050  phenotype
611672  gene
KEGG: hsa:113235    hsa:113235   

Gene Ontology

GO:0016324 C:apical plasma membrane
GO:0005737 C:cytoplasm
GO:0016021 C:integral to membrane
GO:0005542 F:folic acid binding
GO:0008517 F:folic acid transporter activity
GO:0015884 P:folic acid transport
GO:0015232 F:heme transporter activity
GO:0006879 P:cellular iron ion homeostasis
GO:0046655 P:folic acid metabolic process

References (31)

[1] “Complete sequencing and characterization of 21,243 full-length human cDNAs.”  Ota T.et.al.   14702039
[2] “The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).”  The MGC Project Teamet.al.   15489334
[3] “The full-ORF clone resource of the German cDNA consortium.”  Bechtel S.et.al.   17974005
[4] “Identification of an intestinal heme transporter.”  Shayeghi M.et.al.   16143108
[5] “Identification of an intestinal folate transporter and the molecular basis for hereditary folate malabsorption.”  Qiu A.et.al.   17129779
[6] “Haem carrier protein 1 (HCP1): expression and functional studies in cultured cells.”  Latunde-Dada G.O.et.al.   17156779
[7] “The spectrum of mutations in the PCFT gene, coding for an intestinal folate transporter, that are the basis for hereditary folate malabsorption.”  Zhao R.et.al.   17446347
[8] “Heme carrier protein 1 (HCP1) expression and functional analysis in the retina and retinal pigment epithelium.”  Sharma S.et.al.   17335806
[9] “Functional characterization of human proton-coupled folate transporter/heme carrier protein 1 heterologously expressed in mammalian cells as a folate transporter.”  Nakai Y.et.al.   17475902
[10] “Evaluation of the low-specificity protease elastase for large-scale phosphoproteome analysis.”  Wang B.et.al.   19007248
[11] “Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle.”  Daub H.et.al.   18691976
[12] “A quantitative atlas of mitotic phosphorylation.”  Dephoure N.et.al.   18669648
[13] “Glycoproteomics analysis of human liver tissue by combination of multiple enzyme digestion and hydrazide chemistry.”  Chen R.et.al.   19159218
[14] “A novel loss-of-function mutation in the proton-coupled folate transporter from a patient with hereditary folate malabsorption reveals that Arg 113 is crucial for function.”  Lasry I.et.al.   18559978
[15] “Complete sequencing and characterization of 21,243 full-length human cDNAs.”  Ota T.et.al.   14702039
[16] “The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).”  The MGC Project Teamet.al.   15489334
[17] “The full-ORF clone resource of the German cDNA consortium.”  Bechtel S.et.al.   17974005
[18] “Identification of an intestinal heme transporter.”  Shayeghi M.et.al.   16143108
[19] “Identification of an intestinal folate transporter and the molecular basis for hereditary folate malabsorption.”  Qiu A.et.al.   17129779
[20] “Haem carrier protein 1 (HCP1): expression and functional studies in cultured cells.”  Latunde-Dada G.O.et.al.   17156779
[21] “The spectrum of mutations in the PCFT gene, coding for an intestinal folate transporter, that are the basis for hereditary folate malabsorption.”  Zhao R.et.al.   17446347
[22] “Heme carrier protein 1 (HCP1) expression and functional analysis in the retina and retinal pigment epithelium.”  Sharma S.et.al.   17335806
[23] “Functional characterization of human proton-coupled folate transporter/heme carrier protein 1 heterologously expressed in mammalian cells as a folate transporter.”  Nakai Y.et.al.   17475902
[24] “Evaluation of the low-specificity protease elastase for large-scale phosphoproteome analysis.”  Wang B.et.al.   19007248
[25] “Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle.”  Daub H.et.al.   18691976
[26] “A quantitative atlas of mitotic phosphorylation.”  Dephoure N.et.al.   18669648
[27] “Glycoproteomics analysis of human liver tissue by combination of multiple enzyme digestion and hydrazide chemistry.”  Chen R.et.al.   19159218
[28] “A novel loss-of-function mutation in the proton-coupled folate transporter from a patient with hereditary folate malabsorption reveals that Arg 113 is crucial for function.”  Lasry I.et.al.   18559978
[29] “Properties of the Arg376 residue of the proton-coupled folate transporter (PCFT-SLC46A1) and a glutamine mutant causing hereditary folate malabsorption.”  Mahadeo K.et.al.   20686069
[30] “Functional roles of aspartate residues of the proton-coupled folate transporter (PCFT-SLC46A1); a D156Y mutation causing hereditary folate malabsorption.”  Shin D.S.et.al.   20805364
[31] “Identification of novel mutations in the proton-coupled folate transporter (PCFT-SLC46A1) associated with hereditary folate malabsorption.”  Shin D.S.et.al.   21333572

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FASTA formatted sequence
1:	MEGSASPPEK PRARPAAAVL CRGPVEPLVF LANFALVLQG PLTTQYLWHR FSADLGYNGT 
61:	RQRGGCSNRS ADPTMQEVET LTSHWTLYMN VGGFLVGLFS STLLGAWSDS VGRRPLLVLA 
121:	SLGLLLQALV SVFVVQLQLH VGYFVLGRIL CALLGDFGGL LAASFASVAD VSSSRSRTFR 
181:	MALLEASIGV AGMLASLLGG HWLRAQGYAN PFWLALALLI AMTLYAAFCF GETLKEPKST 
241:	RLFTFRHHRS IVQLYVAPAP EKSRKHLALY SLAIFVVITV HFGAQDILTL YELSTPLCWD 
301:	SKLIGYGSAA QHLPYLTSLL ALKLLQYCLA DAWVAEIGLA FNILGMVVFA FATITPLMFT 
361:	GYGLLFLSLV ITPVIRAKLS KLVRETEQGA LFSAVACVNS LAMLTASGIF NSLYPATLNF 
421:	MKGFPFLLGA GLLLIPAVLI GMLEKADPHL EFQQFPQSP