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Translation in Plasmodium falciparum

The objective of this project is to study the enzymes and RNAs of the translational machinery of Plasmodium falciparum with the aim of increasing fundamental knowledge on the protein synthesis system of this pathogen and developing new anti-malarial strategies over time. Indeed, apart from the genomic data on Plasmodium, our understanding of the mechanism of action of the parasite aminoacyl-tRNA synthetases and transfer RNAs is virtually non-existent. The approaches we propose to develop also examine the potential interactions between the parasite and its host. This project will increase basic knowledge about translation in Plasmodium falciparum and in humans. It may eventually lead to the identification of new effective pharmaceutical targets against malaria.

We study the functional and structural properties of various human and plasmodial aminoacyl-tRNA synthetases selected for their idiosyncratic characteristics. Access to the biological material of Plasmodium (including tRNAs), the expression of parasite aminoacyl-tRNA synthetases in Escherichia coli and the purification of the corresponding recombinant proteins constitute essential initial steps in determining the functional and structural properties of the selected aminoacylation systems. Our first results concern the systems of aspartic acid, asparagine and tyrosine. Other cytoplasmic and apicoplastic systems are under study.

Another component of this project addresses a key issue on host-pathogen interactions and focuses on the influence of host tRNAs on the life cycle of Plasmodium. We have recently shown that a protein called tRip for “tRNA import protein” acts as a mediator for the entry of tRNA into the parasite and that this mechanism is crucial for infection. In addition, the gene that encodes tRip is specific to apicomplex parasites, such as Plasmodium, Toxoplasma and Cryptosporidium. The tRip protein is located in the membrane at the surface of the parasite, with its tRNA-binding domain exposed to the outside. The aim of this project is to deepen our understanding of the function and structure of this unique tRNA import mechanism specific to these parasites in order to understand how host tRNAs are selected, transported in Plasmodium and affect the expression of genes. We wish to arrive at a detailed functional and structural description of this new tRNA import process by determining the three-dimensional structure of tRip, its mode of interaction with tRNAs and the nature of its possible intracellular protein partners. This project, which is oriented towards fundamental research, is guided by key biological questions in the field of microbiology.

Image Frugier_th2

Model of tRip in the plasmic membrane of Plasmodium falciparum. The dimer of tRip is anchored in the lipid bilayer through a trans-membrane helix (purple). The N-terminus domains (grey) are exposed to the cytoplasm of the parasite, whereas the C-terminus domains (green) recognizing the tRNAs point towards the outside

The main conceptual results of this work will shed new light on the unique process of importing tRNAs in Plasmodium. We will then address the fundamental question of the development of new antimalarial molecules based on our biochemical and structural results.