Levray, Yvette S.; (2024) Molecular mechanisms of protein export and host cell modification by the malaria parasite. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

During the asexual stage of their life cycle, Plasmodium parasites invade human erythrocytes. Parasites extensively modify their host erythrocytes to survive, contributing to the pathogenicity of malaria. These modifications are performed by parasite proteins exported into the host cell. Despite of the significance of exported proteins in the pathogenicity of the disease, fundamental questions remain about how exported proteins traverse through the secretory pathway and into the red blood cell. This work aimed to address how exported membrane proteins traverse the secretory pathway. Our experiments suggest that a model exported transmembrane protein translocates across the endoplasmic reticulum membrane and into the lumen in a soluble form instead of spanning the membrane bilayer. We also set out to investigate how exported proteins are targeted within the host cell. Previous work in our group determined that exported proteins containing lowcomplexity, lysine-rich residues target to the periphery of the red blood cell in P. falciparum. We show that this phenomenon is shared by other human Plasmodium species. In addition, an exported protein that may be important for trafficking between Maurer’s clefts and the erythrocyte is identified. To characterise these low-complexity sequences and their potential interactions, a protein-fragment complementation assay was designed to study protein-protein interactions. This method demonstrates the utility of split-dihydrofolate reductase used to study protein-protein interactions in Plasmodium for the first time. While the assay was unsuccessful to study low-complexity sequences, we show that it can be used for the characterisation of protein interactions in the parasite.

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