ArticleBiochimica et biophysica acta2011
Vulnerability of the cysteine-less proton-coupled folate transporter (PCFT-SLC46A1) to mutational stress associated with the substituted cysteine accessibility method.
Article in Biochimica et biophysica acta, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 13 citations in OpenAlex.
- Substituted-cysteine accessibility and cross-linking identify an exofacial cleft in the 7th and 8th helices of the proton-coupled folate transporter (SLC46A1).American journal of physiology. Cell physiology · 2018Article
- 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
- 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
- The proton-coupled folate transporter: physiological and pharmacological roles.Current opinion in pharmacology · 2013Review
- Role of the fourth transmembrane domain in proton-coupled folate transporter function as assessed by the substituted cysteine accessibility method.American journal of physiology. Cell physiology · 2013Article
- Substitution of transmembrane domain Cys residues alters pH(o)-sensitive anion transport by AE2/SLC4A2 anion exchanger.Pflugers Archiv : European journal of physiology · 2013Article
- Delineating the extracellular water-accessible surface of the proton-coupled folate transporter.PloS one · 2013Article
- Identification of a disulfide bridge important for transport function of SNAT4 neutral amino acid transporter.PloS one · 2013Article
- Functional roles of the A335 and G338 residues of the proton-coupled folate transporter (PCFT-SLC46A1) mutated in hereditary folate malabsorption.American journal of physiology. Cell physiology · 2012Article
- Random mutagenesis of the proton-coupled folate transporter (SLC46A1), clustering of mutations, and the bases for associated losses of function.The Journal of biological chemistry · 2011Article
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
The proton-coupled transporter (PCFT) mediates intestinal folate absorption and folate transport from blood across the choroid plexus. The membrane topology of PCFT has been defined using the substituted cysteine accessibility method; an intramolecular disulfide bond between the Cys 66 and 298 residues, in the first and fourth extracellular loops, respectively, is present but not essential for function. The current report describes Lys 422 mutations (K422C, K422E) that have no effect on transport activity when introduced into wild-type PCFT but result in a marked loss of activity when introduced into a Cys-less PCFT which is otherwise near-fully functional. The loss of activity of both mutant PCFTs was shown to be due to impaired protein stability and expression. Additional studies were conducted with the K422C mutation in Cys-less PCFT. The impact of re-introduction of one, two, three or five, Cys residues was assessed. While there were some differences in the impact of the different Cys residues re-introduced, restoration was attributed more to a cumulative effect rather than the specific role of individual Cys residues. Preservation of the Cys66-Cys298 intramolecular disulfide bond was not required for stability of the K422C protein. These observations are relevant to studies with Cys-less transporters utilized for the characterization of proteins with the substituted cysteine accessibility method and indicate that functional defects detected in a Cys-less protein, when the tertiary structure of the molecule is stressed, are not necessarily relevant to the wild-type protein.
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