| 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. | |
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MedLine Citation:
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PMID: 18559978 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Hereditary folate malabsorption (HFM) patients harbor inactivating mutations including R113S in the proton-coupled folate transporter (PCFT), an intestinal folate transporter with optimal activity at acidic pH. Here we identified and characterized a novel R113C mutation residing in the highly conserved first intracellular loop of PCFT. Stable transfectants overexpressing a Myc-tagged wild-type (WT) and mutant R113C PCFT displayed similar transporter targeting to the plasma membrane. However, whereas WT PCFT transfectants showed a 22-fold increase in [(3)H]folic acid influx at pH 5.5, R113C or mock transfectants showed no increase. Moreover, WT PCFT transfectants displayed a 50% folic acid growth requirement concentration of 7 nM, whereas mock and R113C transfectants revealed 24- to 27-fold higher values. Consistently, upon fluorescein-methotrexate labeling, WT PCFT transfectants displayed a 50% methotrexate displacement concentration of 50 nM, whereas mock and R113C transfectants exhibited 12- to 14-fold higher values. Based on the crystal structure of the homologous Escherichia coli glycerol-3-phosphate transporter, we propose that the cationic R113 residue of PCFT is embedded in a hydrophobic pocket formed by several transmembrane helices that may be part of a folate translocation pore. These findings establish a novel loss of function mutation in HFM residing in an intracellular loop of PCFT crucial for folate transport. |
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Authors:
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Inbal Lasry; Bluma Berman; Rachel Straussberg; Yael Sofer; Hanna Bessler; Mohamad Sharkia; Fabian Glaser; Gerrit Jansen; Stavit Drori; Yehuda G Assaraf |
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Publication Detail:
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Type: Case Reports; In Vitro; Journal Article; Research Support, Non-U.S. Gov't Date: 2008-06-17 |
Journal Detail:
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Title: Blood Volume: 112 ISSN: 1528-0020 ISO Abbreviation: Blood Publication Date: 2008 Sep |
Date Detail:
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Created Date: 2008-08-26 Completed Date: 2008-09-30 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 7603509 Medline TA: Blood Country: United States |
Other Details:
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Languages: eng Pagination: 2055-61 Citation Subset: AIM; IM |
Affiliation:
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The Fred Wyszkowski Cancer Research Laboratory, Department of Biology, Technion-Israel Institute of Technology, Haifa, Israel. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Amino Acid Sequence Animals Arginine / chemistry Base Sequence Binding Sites / genetics CHO Cells Carrier Proteins / chemistry, genetics*, metabolism Cell Membrane / metabolism Child Consanguinity Cricetinae Cricetulus DNA Primers / genetics Folic Acid / metabolism* Homozygote Humans Hydrogen-Ion Concentration Malabsorption Syndromes / genetics*, metabolism* Methotrexate / metabolism Models, Molecular Molecular Sequence Data Mutagenesis, Site-Directed Point Mutation* Protein Conformation Receptors, Cell Surface / chemistry, deficiency, genetics*, metabolism Recombinant Proteins / chemistry, genetics, metabolism Sequence Homology, Amino Acid Transfection |
| Chemical | |
Reg. No./Substance:
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0/Carrier Proteins; 0/DNA Primers; 0/Receptors, Cell Surface; 0/Recombinant Proteins; 0/folate-binding protein; 59-05-2/Methotrexate; 59-30-3/Folic Acid; 74-79-3/Arginine |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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