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.
Highlights
The Plasmodium falciparum chloroquine resistance transporter (PfCRT) is a key contributor to multidrug resistance and is essential for the survival of the malaria parasite, yet its natural function remains unresolved
A large collection of metabolites and ions was screened for molecules that interact with the substrate-binding cavity of PfCRT in the Xenopus oocyte system[15]
Our work has provided a definitive resolution of the natural substrates and physiological role of PfCRT, a key contributor to multidrug resistance in the malaria parasite
Summary
The Plasmodium falciparum chloroquine resistance transporter (PfCRT) is a key contributor to multidrug resistance and is essential for the survival of the malaria parasite, yet its natural function remains unresolved. Two PfCRT mutations that arose separately under in vitro drug pressure (C101F and L272F) incur both a fitness cost and a monstrously swollen DV13 These findings indicate that PfCRT is crucial for parasite growth and replication, and for maintaining the osmotic homoeostasis of the DV, its native substrates and function remain unresolved. Attempts to characterise PfCRT in heterologous expression systems have produced wildly disparate results, with it being claimed to function as either a Cl− channel[28,29], a H+ pump[30], a non-specific cation channel[31], an activator of H+ pumps and of non-specific cation channels[31], a glutathione transporter[32], a non-specific transporter of inorganic and organic cations as well as of many other metabolites[33], or an Fe2+/Fe3+ transporter[34] None of these studies undertook experiments with parasites to substantiate that PfCRT exhibited the proposed transport activity in situ and that mediating this activity was the protein’s physiological role
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