Last Updated: 22/02/2024
A vacuolar lipocalin as a candidate regulator of hemoglobin catabolism and hemozoin formation in the malaria parasite
Objectives
This proposal will conduct investigations to identify the interaction partners of PV5 and analyze the consequences of PV5 ablation.
Malaria is a significant burden on the public health and fragile economies of developing countries. The distinct pathology of malaria is caused by the propagation of Plasmodium parasites in the human bloodstream. Here, this unicellular pathogen invades erythrocytes and digests vast amounts of hemoglobin inside a specialized organelle, called the digestive vacuole. During hemoglobin degradation, large quantities of the prosthetic group heme are released, which causes a variety of cytotoxic effects in its unbound form. Thus, the parasite sequesters heme into an inert crystal, the so-called malaria pigment or hemozoin. The factors regulating hemoglobin digestion and heme biomineralization are only poorly understood. A candidate regulator of these processes has been identified, called PV5. Sequence analysis suggests, that PV5 is a lipocalin. Proteins of this family bind diverse ligands in their barrel-like binding pockets and function in a variety of molecular processes. PV5 localizes to the digestive vacuole, where it participates in a soluble protein complex. I bring forward the hypothesis that PV5 is a heme-dependent regulator of the hemoglobin digestion machinery, controlling the rate of hemoglobin catabolism and intracellular heme concentrations. I propose a complementary strategy that approaches PV5 function in the human malaria parasite P. falciparum by reverse genetics and protein interaction studies.
Jan 2019 — Dec 2021
