FORMIN

Structural and functional studies on Plasmodium formins

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 Obiettivo del progetto (Objective)

'Funding is applied to carry out research on formin-mediated regulation and dynamics of actin-based motility of apicomplexan parasites, such as Plasmodium, the causative agent of malaria. Formins are large multi-domain proteins, which regulate microfilament formation by triggering actin monomer addition from actin-profilin complexes at the barbed end. Formins bear two formin homology (FH) domains. Plasmodium FH2 domains are conserved with higher eukaryotes and are responsible for actin binding, while Plasmodium formins contain only putative short FH1 domains with a small number of prolines that could be recognized by proline-rich motif binding proteins, such as profilin. The aim of this study is to find out if these short proline-rich regions in apicomplexan formins are enough for recruiting profilin–actin complexes and to perform structural and biochemical/biophysical characterization of the formins and their binding partners. In addition, crystal and solution structures of the ternary complex actin-profilin-formin will be pursued. These data are expected to provide us with a structural basis for understanding the mechanism of actin-based motility in apicomplexan parasites. The host laboratory has excellent facilities for molecular biology, protein production as well as X-ray crystallography. I myself as the applicant have spacious knowledge in these methods. The planned visit will be the first post-doctoral period for me and will serve as an important step to develop my scientific career.'

Introduzione (Teaser)

According to the World Health Organisation, malaria remains a serious health issue in many countries endemic to the vector and the parasite. With limited intervention strategies currently available, research is looking to understand the biology of the malaria parasite.

Descrizione progetto (Article)

Plasmodium falciparum, the causative agent of malaria is carried through the bites of infected mosquitos into the bloodstream of humans. Current treatment entails the administration of artemisinin-based combination therapies. However, the emergence of drug-resistant parasites has urged the scientific community to revisit several aspects of the malaria parasite and find novel targets for therapy.

Alongside that notion, the EU-funded 'Structural and functional studies on Plasmodium formins' (FORMIN) project set out to investigate the motility of the parasite during infection. Particular focus was given on formins, a group of proteins that participate in and regulate the formation of the actin cytoskeleton to control cell movement.

Researchers successfully expressed and purified the two Plasmodium formin isoforms. Using X-ray-based methodologies, they were able to elucidate the structure of Plasmodium formins at low resolution. Although crystallisation studies are required to provide the detailed structure of the molecule, electron microscopy analysis revealed the ability of formins to bundle actin filaments. Formin 2 also interacted with profilin, potentially participating in the dynamic turnover and restructuring of the actin cytoskeleton of the parasite.

The work by the FORMIN project offered a structural basis for understanding the mechanism of actin-based motility in malaria parasites. This information opens up new avenues for therapeutic exploitation through modulation of the parasite motility.