The natural function of the malaria parasite’s chloroquine resistance transporter

Sarah H. Shafik, Simon A. Cobbold, Kawthar Barkat, Sashika N. Richards, Nicole S. Lancaster, Manuel Llinás, Simon J. Hogg, Robert L. Summers, Malcolm J. McConville, Rowena E. Martin

Research output: Contribution to journalArticle

Abstract

The Plasmodium falciparum chloroquine resistance transporter (PfCRT) is a key contributor to multidrug resistance and is also essential for the survival of the malaria parasite, yet its natural function remains unresolved. We identify host-derived peptides of 4-11 residues, varying in both charge and composition, as the substrates of PfCRT in vitro and in situ, and show that PfCRT does not mediate the non-specific transport of other metabolites and/or ions. We find that drug-resistance-conferring mutations reduce both the peptide transport capacity and substrate range of PfCRT, explaining the impaired fitness of drug-resistant parasites. Our results indicate that PfCRT transports peptides from the lumen of the parasite’s digestive vacuole to the cytosol, thereby providing a source of amino acids for parasite metabolism and preventing osmotic stress of this organelle. The resolution of PfCRT’s native substrates will aid the development of drugs that target PfCRT and/or restore the efficacy of existing antimalarials.

Original languageEnglish (US)
Article number3922
JournalNature communications
Volume11
Issue number1
DOIs
StatePublished - Dec 1 2020

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Shafik, S. H., Cobbold, S. A., Barkat, K., Richards, S. N., Lancaster, N. S., Llinás, M., Hogg, S. J., Summers, R. L., McConville, M. J., & Martin, R. E. (2020). The natural function of the malaria parasite’s chloroquine resistance transporter. Nature communications, 11(1), [3922]. https://doi.org/10.1038/s41467-020-17781-6