Nature communications, 2020-08, Vol.11 (1), p.3922-16, Article 3922
2020
Details
- Autor(en) / Beteiligte
- Titel
- The natural function of the malaria parasite's chloroquine resistance transporter
- Ist Teil von
- Nature communications, 2020-08, Vol.11 (1), p.3922-16, Article 3922
- Ort / Verlag
- England: Nature Publishing Group
- Erscheinungsjahr
- 2020
- Link zum Volltext
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 2041-1723eISSN: 2041-1723DOI: 10.1038/s41467-020-17781-6Titel-ID: cdi_doaj_primary_oai_doaj_org_article_e62a9cfeb1b74e3793184dbfb72b16f7
- Format
- –
- Schlagworte
- Amino acids, Animals, Antimalarials - pharmacology, Biological Transport, Active, Chloroquine, Chloroquine - pharmacology, Cytosol, Drug development, Drug resistance, Drug Resistance - genetics, Erythrocytes, Female, Host-Parasite Interactions - genetics, Host-Parasite Interactions - physiology, Humans, Ions, Malaria, Malaria, Falciparum - drug therapy, Malaria, Falciparum - metabolism, Malaria, Falciparum - parasitology, Membrane Transport Proteins - genetics, Membrane Transport Proteins - metabolism, Metabolism, Metabolites, Models, Biological, Multidrug resistance, Mutant Proteins - genetics, Mutant Proteins - metabolism, Mutation, Oligopeptides - metabolism, Oocytes - metabolism, Osmotic stress, Parasite resistance, Parasites, Peptides, Plasmodium falciparum, Plasmodium falciparum - drug effects, Plasmodium falciparum - genetics, Plasmodium falciparum - metabolism, Protein Transport, Protozoan Proteins - genetics, Protozoan Proteins - metabolism, Residues, Substrates, Vector-borne diseases, Xenopus laevis