Reduced folate transporter (SLC19A1)
The protein contains 591 amino acids for an estimated molecular weight of 64868 Da.
Transporter that mediates the import of reduced folates and a subset of cyclic dinucleotides (PubMed:7826387, PubMed:9041240, PubMed:10787414, PubMed:15337749, PubMed:16115875, PubMed:31126740, PubMed:31511694). Has high affinity for N5-methyltetrahydrofolate, the predominant circulating form of folate (PubMed:10787414, PubMed:14609557, PubMed:22554803). Also able to mediate the import of antifolate drug methotrexate (PubMed:7615551, PubMed:7641195, PubMed:9767079, PubMed:22554803). Acts as an importer of immunoreactive cyclic dinucleotides, such as cyclic GMP-AMP (2'-3'-cGAMP), an immune messenger produced in response to DNA virus in the cytosol, and its linkage isomer 3'-3'-cGAMP (PubMed:31126740, PubMed:31511694). Mechanistically, acts as an antiporter, which export of intracellular organic anions to facilitate uptake of its substrates (PubMed:22554803, PubMed:31126740, PubMed:31511694). 5-amino-4-imidazolecarboxamide riboside (AICAR), when phosphorylated to AICAR monophosphate, can serve as an organic anion for antiporter activity (PubMed:22554803). (updated: Nov. 13, 2019)
Protein identification was indicated in the following studies:
- Goodman and co-workers. (2013) The proteomics and interactomics of human erythrocytes. Exp Biol Med (Maywood) 238(5), 509-518.
- Hegedűs and co-workers. (2015) Inconsistencies in the red blood cell membrane proteome analysis: generation of a database for research and diagnostic applications. Database (Oxford) 1-8.
- Bryk and co-workers. (2017) Quantitative Analysis of Human Red Blood Cell Proteome. J Proteome Res. 16(8), 2752-2761.
- D'Alessandro and co-workers. (2017) Red blood cell proteomics update: is there more to discover? Blood Transfus. 15(2), 182-187.
Methods
The following articles were analysed to gather the proteome content of erythrocytes.
The gene or protein list provided in the studies were processed using the ID mapping API of Uniprot in September 2018. The number of proteins identified and mapped without ambiguity in these studies is indicated below.
Only Swiss-Prot entries (reviewed) were considered for protein evidence assignation.
| Publication | Identification 1 | Uniprot mapping 2 | Not mapped / Obsolete | TrEMBL | Swiss-Prot |
|---|---|---|---|---|---|
| Goodman (2013) | 2289 (gene list) | 2278 | 53 | 20599 | 2269 |
| Lange (2014) | 1234 | 1234 | 7 | 28 | 1224 |
| Hegedus (2015) | 2638 | 2622 | 0 | 235 | 2387 |
| Wilson (2016) | 1658 | 1528 | 170 | 291 | 1068 |
| d'Alessandro (2017) | 1826 | 1817 | 2 | 0 | 1815 |
| Bryk (2017) | 2090 | 2060 | 10 | 108 | 1942 |
| Chu (2018) | 1853 | 1804 | 55 | 362 | 1387 |
1 as available in the article and/or in supplementary material
2 uniprot mapping returns all protein isoforms as one entry
The compilation of older studies can be retrieved from the Red Blood Cell Collection database.
The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.
This protein is annotated as membranous in Gene Ontology, is annotated as membranous in UniProt, is predicted to be membranous by TOPCONS.
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| Variant | Description |
|---|---|
| dbSNP:rs1051266 | |
| dbSNP:rs35786590 |
No binding partner found
Biological Process
Cyclic-GMP-AMP transmembrane import across plasma membrane
Female pregnancy
Folate import across plasma membrane
Folate transmembrane transport
Folic acid metabolic process
Folic acid transport
Methotrexate transport
Organic anion transport
Small molecule metabolic process
Transmembrane transport
Transport across blood-brain barrier
Vitamin metabolic process
Water-soluble vitamin metabolic process
The reference OMIM entry for this protein is 600424
Solute carrier family 19 (folate transporter), member 1; slc19a1
Folate transporter; folt
Reduced folate carrier 1; rfc1
Intestinal folate carrier 1; ifc1
DESCRIPTION
Transport of folate compounds into mammalian cells can occur via receptor-mediated (see 136430) or carrier-mediated mechanisms. A functional coordination between these 2 mechanisms has been proposed to be the method of folate uptake in certain cell types. Methotrexate (MTX) is an antifolate chemotherapeutic agent that is actively transported by the carrier-mediated uptake system. RFC1 plays a role in maintaining intracellular concentrations of folate.CLONING
Several groups independently cloned cDNAs encoding the 591-amino acid human folate transporter. Using a mouse reduced folate carrier (RFC) partial cDNA as a probe, Wong et al. (1995) cloned a human RFC cDNA from a library prepared from MTX transport-upregulated erythroleukemia cells. Using homologous murine cDNAs as probes, Williams and Flintoff (1995), Prasad et al. (1995), and Nguyen et al. (1997) independently isolated human folate transporter cDNAs from lymphoblast, placenta, and small intestine libraries, respectively. Prasad et al. (1995) reported that the human folate transporter, which they symbolized FOLT, had 65% amino acid sequence identity to mouse and hamster folate transporters. When transfected into COS-1 and HeLa cells, the human FOLT cDNA caused a significant increase in the uptake of 5-methyltetrahydrofolate. By Northern blot analysis, mRNA transcripts hybridizing to the human FOLT cDNA were detected in placenta and liver and also in several cell lines of human origin. The principal transcript was approximately 2.7 kb. Williams and Flintoff (1995) and Wong et al. (1995) observed that human folate transport cDNAs expressed in MTX transport-deficient Chinese hamster ovary cells restored MTX transport and sensitivity. Nguyen et al. (1997) injected human intestinal folate carrier-1 (IFC1) cRNA into Xenopus oocytes and observed increased uptake of methyltetrahydrofolic acid. Northern blot analysis revealed that the IFC1 gene was expressed as a 3.3-kb mRNA at a high level in placenta and at lower levels in a variety of other tissues, including the small intestine. In situ hybridization of thin sections of intestinal epithelia demonstrated IFC1 expression localized to the villus and crypt cells, particularly the upper half of the villi.GENE FUNCTION
In luminal epithelial cells isolated from mouse small intestine, Chiao et al. (1997) found increased PH-dependent folate influx associated with RFC1 gene expression in the form of a 2.5-kb transcript and a 58-kD brush border membrane protein detected by folate-based affinity labeling and with antibodies against the transporter. The authors concluded that RFC1 mediates intestinal folate transport.GENE STRUCTURE
Point mutations in the reduced folate carrier-1 gene and alterations resulting in the downregulation of its message are major factors in the resistance to antifolate chemotherapeutic agents. As a framework for understanding the significance of such changes in relation to gene expression and function, Williams and Flintoff (1998) described the organization of the RFC1 gene from human lymphoblasts. They found that the gene contains 5 exons (2 to 6) coding for protein. At least 4 5-prime exons, used in a mutually exclusive manner in the production of RFC1 message from lymphoblast cells, are spliced to exon 2, which contains the translational start site. Semiquantitative PCR indicated that exon 1 is preferentially used. The major transcriptional start site was mapped ... More on the omim web site
Dec. 2, 2019: Protein entry updated
Automatic update: Entry updated from uniprot information.
Aug. 20, 2019: Protein entry updated
Automatic update: Entry updated from uniprot information.
Feb. 2, 2018: Protein entry updated
Automatic update: Uniprot description updated
Dec. 19, 2017: Protein entry updated
Automatic update: Uniprot description updated
Nov. 23, 2017: Protein entry updated
Automatic update: Uniprot description updated
March 16, 2016: Protein entry updated
Automatic update: OMIM entry 600424 was added.
Feb. 25, 2016: Protein entry updated
Automatic update: model status changed
Feb. 24, 2016: Protein entry updated
Automatic update: model status changed
Jan. 24, 2016: Protein entry updated
Automatic update: model status changed