Gene Ontology annotation through association of InterPro records with GO terms
Gene Ontology annotation based on Enzyme Commission mapping
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
Electronic Gene Ontology annotations created by ARBA machine learning models
Combined Automated Annotation using Multiple IEA Methods
Na(+) regulation in the malaria parasite Plasmodium falciparum involves the cation ATPase PfATP4 and is a target of the spiroindolone antimalarials.
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PfATP4 is a plasma membrane Na(+) efflux pump of the intraerythrocytic parasite, related to the ENA Na(+)-ATPases of fungi and plants, and is the target of the spiroindolone antimalarials.
"The results are consistent with the hypothesis that PfATP4 is a plasma membrane Na+ efflux pump, similar to the ENA Na+-ATPases of other lower eukaryotes, and a target of the spiroindolone class of antimalarials."
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The earlier assignment of PfATP4 as a Ca(2+)-ATPase was never confirmed and no Ca(2+) transport has been demonstrated.
"There is evidence for it having an associated Ca2+-dependent ATPase activity (Krishna et al., 2001); however, this has not been confirmed (Rottmann et al., 2010), and a Ca2+ transport function has not been demonstrated directly."
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Sequence similarity between ENA-type Na(+)-ATPases and SERCA/PMCA Ca(2+) pumps has repeatedly caused Na(+)-ATPases to be misannotated as Ca(2+)-ATPases.
"The ENA ATPases are closely related to sarcoplasmic/endoplasmic reticulum Ca2+-ATPases (SERCA) and plasma membrane Ca2+-ATPases (PMCA), leading some Na+-ATPases within this family to be misannotated as Ca2+-ATPases (Benito et al., 2002)."
Biochemical characterization and chemical inhibition of PfATP4-associated Na(+)-ATPase activity in Plasmodium falciparum membranes.
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The cipargamin-sensitive ATPase activity of P. falciparum membranes behaves as a Na(+) transporter and is insensitive to K(+) and Ca(2+), though sensitive to pH.
"Characterization of the cipargamin-sensitive ATPase activity yielded data consistent with PfATP4 being a Na + transporter that is sensitive to physiologically relevant perturbations of pH, but not of [K + ] or [Ca 2+ ]."
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K(+) has no effect on PfATP4-associated ATPase activity across the whole physiological range, arguing against a K(+)-transport function.
"K + was without effect on PfATP4-associated ATPase activity when present at concentrations ranging from 0 to 150 m m ."
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The mature trophozoite must export Na(+) across its own plasma membrane to keep cytosolic Na(+) low despite the Na(+)-rich infected-erythrocyte cytosol.
"Thus, despite its intracellular location, the mature trophozoite finds itself in a high-Na + environment and must efflux Na + ions across its plasma membrane to maintain a low cytosolic Na + concentration ([Na + ] cyt )."
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PfATP4 is a plasma membrane type II P-type ATPase of a subclass restricted to apicomplexan parasites.
"These parasites were characterized by mutations in PfATP4, a plasma membrane type II P-type ATPase reported to belong to a subclass unique to apicomplexan parasites ( 3 )."
A G358S mutation in the Plasmodium falciparum Na(+) pump PfATP4 confers clinically-relevant resistance to cipargamin.
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The clinically selected G358S mutation lowers the affinity of PfATP4 for Na(+) and raises the resting cytosolic Na(+) concentration of the parasite, linking the protein's transport parameters to the parasite's Na(+) set point.
"The G358S mutation reduces the affinity of PfATP4 for Na+ and is associated with an increase in the parasite's resting cytosolic [Na+]."
Cell Swelling Induced by the Antimalarial KAE609 (Cipargamin) and Other PfATP4-Associated Antimalarials.
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Structurally diverse PfATP4-targeting compounds cause swelling of isolated blood-stage parasites and of infected erythrocytes, the osmotic consequence of Na(+) accumulation when the pump is inhibited.
"Here we show that six structurally diverse PfATP4-associated compounds, including the clinical candidate KAE609 (cipargamin), induce swelling of both isolated blood-stage parasites and intact parasitized erythrocytes."
Endogenous structure of antimalarial target PfATP4 reveals an apicomplexan-specific P-type ATPase modulator.
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A 3.7 A cryo-EM structure of endogenously purified PfATP4 resolves its ATP- and ion-binding sites.
"Our structure reveals the molecular details of ATP and ion-binding sites in PfATP4 and provides a structural framework for understanding the spatial organization of resistance-conferring mutations."
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The cation-binding site lies between TM4, TM5, TM6 and TM8 as in SERCA, with conserved Na(+)-coordinating side chains.
"The ion-binding site within the TMD is located between TM4, TM5, TM6 and TM8, similar to that of SERCA24,25(Fig. 2c)."
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PfATP4 forms a complex with an apicomplexan-specific partner, PfABP, on which its stability depends; PfABP knockdown depletes PfATP4 and kills the parasite.
"Interestingly, PfABP knockdown also led to a marked reduction in PfATP4 protein levels within 24 h, highlighting a strict dependency of PfATP4 stability on its association with PfABP (Fig. 4d, Supplementary Fig. 4b, c)."
(+)-SJ733, a clinical candidate for malaria that acts through ATP4 to induce rapid host-mediated clearance of Plasmodium.
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Inhibition of ATP4 by (+)-SJ733 clears parasites in vivo by inducing eryptosis/senescence of infected erythrocytes, a host-mediated consequence of disrupting parasite Na(+) regulation rather than a function of ATP4 itself.
"(+)-SJ733 cleared parasites in vivo as quickly as artesunate by specifically inducing eryptosis/senescence in infected, treated erythrocytes."
Spiroindolones, a potent compound class for the treatment of malaria.
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Resistance to the spiroindolones is conferred by nonsynonymous mutations in the gene encoding PfATP4, identifying the protein as the target.
"Spiroindolones rapidly inhibit protein synthesis in P. falciparum, an effect that is ablated in parasites bearing nonsynonymous mutations in the gene encoding the P-type cation-transporter ATPase4 (PfATP4)."
Mutations in the P-type cation-transporter ATPase 4, PfATP4, mediate resistance to both aminopyrazole and spiroindolone antimalarials.
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Independent chemotypes (aminopyrazoles and spiroindolones) select overlapping resistance mutations in PfATP4, consistent with a shared target.
"Mutations in the P-type cation-transporter ATPase 4, PfATP4, mediate resistance to both aminopyrazole and spiroindolone antimalarials."
A 4-cyano-3-methylisoquinoline inhibitor of Plasmodium falciparum growth targets the sodium efflux pump PfATP4.
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A further chemotype inhibits PfATP4-associated Na(+)-ATPase activity, reinforcing the identification of the protein as a sodium efflux pump.
"A 4-cyano-3-methylisoquinoline inhibitor of Plasmodium falciparum growth targets the sodium efflux pump PfATP4."
Expression and functional characterization of a Plasmodium falciparum Ca2+-ATPase (PfATP4) belonging to a subclass unique to apicomplexan organisms.
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PfATP4 expressed in Xenopus oocytes showed a Ca(2+)-stimulated ATPase activity over an unusually broad range of free Ca(2+), the basis of the original (and now superseded) assignment of PfATP4 as a Ca(2+)-ATPase.
"The Ca(2+)-dependent ATPase activity of PfATP4 is stimulated by a much broader range of [Ca(2+)](free) (3.2-320 micrometer) than are an avian SERCA1 pump or rabbit SERCA 1a (maximal activity < 10 micrometer)."
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PfATP4 defines a P-type ATPase subclass unique to apicomplexan organisms.
"This analysis suggests that PfATP4 defines a novel subclass of Ca(2+)-ATPases unique to apicomplexan organisms and therefore offers potential as a drug target."
Analysis of a cation-transporting ATPase of Plasmodium falciparum.
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The original cloning of PfATPase4 localised the protein to discrete compartments at the periphery of the parasite across asexual stages, including free merozoites.
"Immunofluorescence microscopy reveals that the PfATPase4 protein is concentrated in discrete compartments at the periphery of the parasite."