Journal article

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 Llinas, Simon J Hogg, Robert L Summers, Malcolm J McConville, Rowena E Martin

Nature Communications | NATURE PUBLISHING GROUP | Published : 2020

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 fr..

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Grants

Awarded by Australian Research Council


Awarded by National Health and Medical Research Council


Awarded by National Institutes of Health


Funding Acknowledgements

We thank Prof David Fidock for providing the transfectant P. falciparum lines, Prof Jean Chmielewski for providing Q<INF>2</INF>C, Prof Kiaran Kirk for providing several of the radiolabelled 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'Ore'al 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.).