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Regulation of a secreted phospholipid transfer protein of the malaria parasite Plasmodium falciparum

Project supervisor – Mike Blackman

Division of Parasitology

We are interested in the molecular mechanisms by which the malaria parasite Plasmodium falciparum interacts with its host erythrocyte. After invading the cell, the parasite exports many proteins beyond the boundaries of its own plasma membrane to modulate various properties of the host erythrocyte, including its deformability, permeability and adhesiveness. Furthermore, the parasite induces the formation of membranous compartments within the erythrocyte cytosol that are important for nutrient uptake and protein transport to the erythrocyte surface. However, the function of most of the exported proteins and their role in the growth and development of the parasite remains unknown. Identification of the biochemical and cellular functions of exported malarial proteins will provide insight into interactions between the parasite and the host cell and may uncover valuable drug targets, as many of the exported proteins have no similarity to human proteins.

Using a bioinformatics approach, we have found that the exported P. falciparum protein PFA0210c is a phospholipid transfer protein which may play a role in the formation of the membranous compartment inside the infected erythrocyte by delivering the required phospholipids. Unusually, PFA0210c has a C-terminal extension beyond its steroidogenic acute regulatory protein-related lipid transfer (START) domain that is involved in regulating its activity; recombinant forms of the protein lacking this extension are much more active in in vitro phospholipid transfer assays. This regulation is likely important for PFA0210c function and parasite development. Determining exactly how this part of the protein regulates the phospholipid transfer activity will shed light on its cellular function.

This project aims to determine how the C terminus of PFA0210c regulates its function through identification of the residues that are required for this regulation, by identifying parasite and/or host cell proteins that bind to this region, by investigating the proteolytic maturation of the protein in the parasite and (time permitting) initiating crystallization trials aimed at determining the 3D structure of the protein.