Functional studies of the <italic>Plasmodium falciparum</italic> translationally controlled tumor protein.

Abstract

The Translationally Controlled Tumor Proteins (TCTPs) are a family of proteins whose functions are still largely unknown. The <italic> Plasmodium falciparum</italic> TCTP was first identified in studies of the mechanism of action of the antimalarial artemisinin. These studies demonstrated that TCTP reacts with artemisinin both <italic>in situ</italic> and <italic> in vitro</italic> in the presence of hemin. <italic>In vitro</italic>, the binding of drug to protein increases with increasing drug concentration, plateauing at approximately one drug per TCTP molecule. This binding also increases with increases in hemin concentration. By Scatchard analysis, TCTP was found to have 2 hemin binding sites with dissociation constant of 18 muM. Subcellular localization by immunofluorescence and immunoelectron microscopy suggests that the malarial TCTP is present in both the cytoplasm and food vaculoar membrane. Like other TCTPs, <italic>P. falciparum</italic> TCTP appears to binds calcium. Several studies have shown that the severity of cerebral malaria may be a result of an overactive host immune response such as an elevation in the production of histamine. This led us to investigate whether TCTP found in patient plasma, was associated with disease severity and might elicit histamine secretion. Malaria infected patients from Malawi had TCTP in plasma with mean levels of 2.33 +/- 0.995 mug per ml. No statistically significant difference was found in plasma TCTP levels from patients with different disease severities or levels of parasitemia, but the sample size was small. Results from <italic> in vitro</italic> parasite cultures suggest that the TCTP found in patient plasma was the result of infected red blood cell lysis which occurs during schizogony. Further studies on physiological role of TCTP may help to understand the mechanism of action of artemisinin and the pathogenesis of malaria.