ArticleThe Journal of biological chemistry2012
Identification and functional impact of homo-oligomers of the human proton-coupled folate transporter.
Article in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed, 35 citations in OpenAlex.
- Structure and function ofProceedings of the National Academy of Sciences of the United States of America · 2024Article
- Role of Mitochondrial and Cytosolic Folylpolyglutamate Synthetase in One-Carbon Metabolism and Antitumor Efficacy of Mitochondrial-Targeted Antifolates.Molecular pharmacology · 2024Article
- Biology and therapeutic applications of the proton-coupled folate transporter.Expert opinion on drug metabolism & toxicology · 2022Article
- The evolving biology of the proton-coupled folate transporter: New insights into regulation, structure, and mechanism.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2022Review
- Structures and General Transport Mechanisms by the Major Facilitator Superfamily (MFS).Chemical reviews · 2021Article
- Folate transporter dynamics and therapy with classic and tumor-targeted antifolates.Scientific reports · 2021Article
- Flavonol-mediated stabilization of PIN efflux complexes regulates polar auxin transport.The EMBO journal · 2021Article
- Impact of nanodisc lipid composition on cell-free expression of proton-coupled folate transporter.PloS one · 2021Article
- Identification of the amino acid residue responsible for the myricetin sensitivity of human proton-coupled folate transporter.Scientific reports · 2019Article
- Regulation of differential proton-coupled folate transporter gene expression in human tumors: transactivation by KLF15 with NRF-1 and the role of Sp1.The Biochemical journal · 2019Article
- The promise and challenges of exploiting the proton-coupled folate transporter for selective therapeutic targeting of cancer.Cancer chemotherapy and pharmacology · 2018Review
- Dual Targeting of Epithelial Ovarian Cancer Via Folate Receptor α and the Proton-Coupled Folate Transporter with 6-Substituted Pyrrolo[2,3-Molecular cancer therapeutics · 2017Article
- The proton-coupled folate transporter (PCFT-SLC46A1) and the syndrome of systemic and cerebral folate deficiency of infancy: Hereditary folate malabsorption.Molecular aspects of medicine · 2017Review
- Transporter oligomerization: form and function.Biochemical Society transactions · 2016Review
- Functional and mechanistic roles of the human proton-coupled folate transporter transmembrane domain 6-7 linker.The Biochemical journal · 2016Article
- Role of the tryptophan residues in proton-coupled folate transporter (PCFT-SLC46A1) function.American journal of physiology. Cell physiology · 2016Article
- Targeting Nonsquamous Nonsmall Cell Lung Cancer via the Proton-Coupled Folate Transporter with 6-Substituted Pyrrolo[2,3-d]Pyrimidine Thienoyl Antifolates.Molecular pharmacology · 2016Article
- Experimentally optimized threading structures of the proton-coupled folate transporter.FEBS open bio · 2016Article
- Structural determinants of human proton-coupled folate transporter oligomerization: role of GXXXG motifs and identification of oligomeric interfaces at transmembrane domains 3 and 6.The Biochemical journal · 2015Article
- Substituted cysteine accessibility reveals a novel transmembrane 2-3 reentrant loop and functional role for transmembrane domain 2 in the human proton-coupled folate transporter.The Journal of biological chemistry · 2014Article
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
Abstract
The proton-coupled folate transporter (PCFT; SLC46A1) is a proton-folate symporter that is abundantly expressed in solid tumors and normal tissues, such as duodenum. The acidic pH optimum for PCFT is relevant to intestinal absorption of folates and could afford a means of selectively targeting tumors with novel cytotoxic antifolates. PCFT is a member of the major facilitator superfamily of transporters. Because major facilitator superfamily members exist as homo-oligomers, we tested this for PCFT because such structures could be significant to PCFT mechanism and regulation. By transiently expressing PCFT in reduced folate carrier- and PCFT-null HeLa (R1-11) cells and chemical cross-linking with 1,1-methanediyl bismethanethiosulfonate and Western blotting, PCFT species with molecular masses approximating those of the PCFT dimer and higher order oligomers were detected. Blue native polyacrylamide gel electrophoresis identified PCFT dimer, trimer, and tetramer forms. PCFT monomers with hemagglutinin and His(10) epitope tags were co-expressed in R1-11 cells, solubilized, and bound to nickel affinity columns, establishing their physical associations. Co-expressing YPet and ECFP*-tagged PCFT monomers enabled transport and fluorescence resonance energy transfer in plasma membranes of R1-11 cells. Combined wild-type (WT) and inactive mutant P425R PCFTs were targeted to the cell surface by surface biotinylation/Western blots and confocal microscopy and functionally exhibited a "dominant-positive" phenotype, implying positive cooperativity between PCFT monomers and functional rescue of mutant by WT PCFT. Our results demonstrate the existence of PCFT homo-oligomers and imply their functional and regulatory impact. Better understanding of these higher order PCFT structures may lead to therapeutic applications related to folate uptake in hereditary folate malabsorption, and delivery of PCFT-targeted chemotherapy drugs for cancer.
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