ArticleAmerican journal of physiology. Cell physiology2013
Role of the fourth transmembrane domain in proton-coupled folate transporter function as assessed by the substituted cysteine accessibility method.
Article in American journal of physiology. Cell physiology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 23 citations in OpenAlex.
- 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
- Article
- Impact of nanodisc lipid composition on cell-free expression of proton-coupled folate transporter.PloS one · 2021Article
- A proton-coupled folate transporter mutation causing hereditary folate malabsorption locks the protein in an inward-open conformation.The Journal of biological chemistry · 2020Article
- Identification of the amino acid residue responsible for the myricetin sensitivity of human proton-coupled folate transporter.Scientific reports · 2019Article
- Substitutions that lock and unlock the proton-coupled folate transporter (PCFT-SLC46A1) in an inward-open conformation.The Journal of biological chemistry · 2019Article
- The promise and challenges of exploiting the proton-coupled folate transporter for selective therapeutic targeting of cancer.Cancer chemotherapy and pharmacology · 2018Review
- Residues in the eighth transmembrane domain of the proton-coupled folate transporter (SLC46A1) play an important role in defining the aqueous translocation pathway and in folate substrate binding.Biochimica et biophysica acta. Biomembranes · 2017Article
- Impact of posttranslational modifications of engineered cysteines on the substituted cysteine accessibility method: evidence for glutathionylation.American journal of physiology. Cell physiology · 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
- 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
- Identification of an Extracellular Gate for the Proton-coupled Folate Transporter (PCFT-SLC46A1) by Cysteine Cross-linking.The Journal of biological chemistry · 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
- Identification of Tyr residues that enhance folate substrate binding and constrain oscillation of the proton-coupled folate transporter (PCFT-SLC46A1).American journal of physiology. Cell physiology · 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
- The major facilitative folate transporters solute carrier 19A1 and solute carrier 46A1: biology and role in antifolate chemotherapy of cancer.Drug metabolism and disposition: the biological fate of chemicals · 2014Review
- Biology of the major facilitative folate transporters SLC19A1 and SLC46A1.Current topics in membranes · 2014Review
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4 authors at 1 institution in 1 country.
Funding
Abstract
The proton-coupled folate transporter (PCFT, SLC46A1) mediates folate transport across the apical brush-border membrane of the proximal small intestine and the basolateral membrane of choroid plexus ependymal cells. Two loss-of-function mutations in PCFT, which are the basis for hereditary folate malabsorption, have been identified within the fourth transmembrane domain (TMD4) in subjects with this disorder. We have employed the substituted Cys accessibility method (SCAM) to study the accessibilities of all residues in TMD4 and their roles in folate substrate binding to the carrier. When residues 146-167 were replaced by Cys, all except R148C were expressed at the cell surface. Modification of five of these substituted Cys residues (positions 147, 152, 157, 158, and 161) by methanethiosulfonate (MTS) reagents led to reduction of PCFT function. All five residues could be labeled with N-biotinylaminoethyl-MTS, and this could be blocked by the high-affinity PCFT substrate pemetrexed. Pemetrexed also protected PCFT mutant function from inhibitory modification of the substituted Cys at positions 157, 158, and 161 by a MTS. The findings indicate that these five residues in TMD4 are accessible to the aqueous translocation pathway, play a role in folate substrate binding, and are likely located within or near the folate binding pocket. A homology model of PCFT places three of these residues, Phe¹⁵⁷, Gly¹⁵⁸, and Leu¹⁶¹, within a breakpoint in the midportion of TMD4, a region that likely participates in alterations in the PCFT conformational state during carrier cycling.
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