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TY - JOUR AU - Shafik, Sarah H. AU - Cobbold, Simon A. AU - Barkat, Kawthar AU - Richards, Sashika N. AU - Lancaster, Nicole S. AU - Llinás, Manuel AU - Hogg, Simon J. AU - Summers, Robert L. AU - McConville, Malcolm J. AU - Martin, Rowena E. PY - 2020 DA - 2020/08/06 TI - The natural function of the malaria parasite’s chloroquine resistance transporter JO - Nature Communications SP - 3922 VL - 11 IS - 1 AB - 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. SN - 2041-1723 UR - https://doi.org/10.1038/s41467-020-17781-6 DO - 10.1038/s41467-020-17781-6 ID - Shafik2020 ER -