TY - JOUR
T1 - The natural function of the malaria parasite’s chloroquine resistance transporter
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.
N1 - Funding Information:
We thank Prof David Fidock for providing the transfectant P. falciparum lines, Prof Jean Chmielewski for providing Q2C, Prof Kiaran Kirk for providing several of the radi-olabelled solutes, Dr Teresa Neeman for assistance with statistical modelling, Dr Adele Lehane for helpful discussions and comments on the manuscript, Megan Nash for conducting preliminary cis-inhibition oocyte assays, and the Canberra Branch of the Australian Red Cross Blood Service for the provision of blood. This work was supported by the Australian Research Council (fellowship 1053082 to R.E.M.), the L’Oreál Australia For Women in Science program (to R.E.M.), the National Health and Medical Research Council (Project Grants 1007035 and 1127338 to R.E.M., fellowship 1154540 to M.J.M., fellowship 1053082 to R.E.M. and fellowship 1120690 to R.L.S.), the National Institutes of Health (1DP2OD001315-01 to M.L.) and the Australian Department of Education (Australian Postgraduate Awards to S.H.S., S.N.R. and R.L.S.).
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
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.
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U2 - 10.1038/s41467-020-17781-6
DO - 10.1038/s41467-020-17781-6
M3 - Article
C2 - 32764664
AN - SCOPUS:85089088337
VL - 11
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 3922
ER -
