Gene Ontology annotation through association of InterPro records with GO terms
Annotation inferences using phylogenetic trees
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
Automatic assignment of GO terms using logical inference, based on on inter-ontology links
Mutations in the P. falciparum digestive vacuole transmembrane protein PfCRT and evidence for their role in chloroquine resistance.
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PfCRT is an integral membrane protein of the parasite digestive vacuole, and point mutations in pfcrt associate with verapamil-reversible chloroquine resistance.
"This transmembrane protein localizes to the parasite digestive vacuole (DV), the site of CQ action, where increased compartment acidification associates with PfCRT point mutations."
The malaria parasite's chloroquine resistance transporter is a member of the drug/metabolite transporter superfamily.
Trafficking of the phosphoprotein PfCRT to the digestive vacuolar membrane in Plasmodium falciparum.
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PfCRT is a phosphoprotein whose sorting to the digestive vacuolar membrane depends on threonine 416.
"phosphorylation of threonine 416 is a possible deciding signal for the sorting of PfCRT to the digestive vacuolar membrane."
Glutathione transport: a new role for PfCRT in chloroquine resistance.
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Mutant pfcrt alleles from chloroquine-resistant parasites, expressed in Xenopus oocytes, selectively transport glutathione.
"We further demonstrate via expression in Xenopus laevis oocytes that the mutant alleles of Pfcrt in CQR parasites selectively transport GSH."
Multiple drugs compete for transport via the Plasmodium falciparum chloroquine resistance transporter at distinct but interdependent sites.
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Mutant PfCRT transports quinine, quinidine and verapamil in addition to chloroquine, with the drugs competing at distinct but interacting sites; the wild-type protein does not transport chloroquine in this system.
"mutant PfCRT also transports quinine, quinidine, and verapamil, indicating that the protein behaves as a multidrug resistance carrier."
Plasmodium falciparum chloroquine resistance transporter is a H+-coupled polyspecific nutrient and drug exporter.
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Purified chloroquine-sensitive and chloroquine-resistant PfCRT reconstituted into proteoliposomes take up organic cations, chloroquine, basic amino acids, polypeptides and polyamines driven by a proton electrochemical gradient.
"All PfCRTs tested actively took up tetraethylammonium, verapamil, CQ, basic amino acids, polypeptides, and polyamines at the expense of an electrochemical proton gradient."
Mutations in the Plasmodium falciparum chloroquine resistance transporter, PfCRT, enlarge the parasite's food vacuole and alter drug sensitivities.
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PfCRT mutations C101F and L272F enlarge the food vacuole and strongly reduce chloroquine transport, linking transporter function to vacuolar homeostasis.
"causing the development of enlarged food vacuoles."
Structure and drug resistance of the Plasmodium falciparum transporter PfCRT.
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The cryo-EM structure of the 7G8 isoform shows resistance mutations lining a central negatively charged cavity, and the isoform transports chloroquine in a membrane-potential- and pH-dependent manner.
"The 7G8 isoform transports CQ in a membrane potential- and pH-dependent manner, consistent with an active efflux mechanism that drives CQ resistance5, but does not transport PPQ."
The natural function of the malaria parasite's chloroquine resistance transporter.
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PfCRT exports host-derived peptides of four to eleven residues from the digestive vacuole to the cytosol, in vitro and in situ, and does not transport other metabolites or ions non-specifically.
"We show that PfCRT functions to export host-derived peptides 4–11 residues in length from the parasite’s DV, and that the protein does not behave as a non-specific transporter of other metabolites and/or ions."
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Peptide export supplies amino acids for parasite growth and prevents osmotic swelling and dysfunction of the digestive vacuole; resistance mutations reduce peptide transport capacity.
"the PfCRT-mediated transport of peptides from the DV to the cytosol serves to (1) provide a source of amino acids to support the parasite’s high growth rate and (2) reduce peptide levels within the DV and thereby prevent the osmotic stress, swelling and dysfunction of this organelle."
Mechanistic basis for multidrug resistance and collateral drug sensitivity conferred to the malaria parasite by polymorphisms in PfMDR1 and PfCRT.
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Chloroquine-resistance-conferring PfCRT isoforms transport chloroquine, lumefantrine and mefloquine, whereas wild-type PfCRT does not.
"demonstrate that these PfCRT isoforms transport all 3 drugs, whereas wild-type PfCRT does not."