Résumé
Schistolysins are aerolysin-like proteins, with 2 genes recently discovered by D. Duval and colleagues in the parasitic flatworm Schistosoma mansoni (unpublished data). This organism is the causative agent of intestinal schistosomiasis, which affected 236 million people worldwide in 2019. In 2020, the WHO called for new therapies to support the action of Praziquantel, the recommended treatment against all forms of schistosomiasis, to eliminate the disease by 2030.Aerolysin-like proteins are found in all kingdoms of life, originating from bacteria, usually as potent attack or defence agents. Schistolysins display structural similarity to this class of proteins, which make them potential β-pore-forming proteins. Our goal is to characterise the structure-function relationships through integrative structural biology. It is produced as a stable octamer, as we were able to identify it by SDS-PAGE, SAXS and native mass spectrometry. We solved the structure of octameric Schi2 at 2.6 Å resolution by X-ray crystallography. It seems to be a pre-pore state by analogy to Aerolysin prepore (PDB: 5JZH) from Aeromonas hydrophila. According to DALI server results, Schi2 displays a very similar structure to Epsilon toxin (PDB: 1UYJ), an aerolysin-like toxin from Clostridium perfringens. Molecular dynamics and liposome leakage experiments will help assay the interaction of Schi2 with membranes and its activity. Also, the purified protein is used for cytotoxicity tests. The combination of structural and functional data should allow us to understand the role of this protein in Schistosoma mansoni, and possibly help develop new therapies against schistosomiasis or other applications.