Pore-forming toxin aerolysin
Many pathogenic bacteria produce protein toxins. The largest class of toxins consists of pore-forming toxins. They are secreted by bacteria in a water-soluble form and after binding to a receptor on target cells, typically eukaryotic cells, they insert and form a pore in their membrane. The cells become leaky, which may eventually lead to cell death. Production of pore-forming proteins is not only found in bacteria but also in other kingdoms of life, where they may assume different roles, e.g. in the defense against pathogens by the immune system. Fresh water bacteria Aeromonas hydrophila produce toxin aerolysin, which is the archetype of a large family of pore-forming proteins present in all kingdoms of life. Secreted water-soluble aerolysin binds to glycosylphosphatidylinositol (GPI) anchored membrane proteins, which are found in all eukaryotes. There, aerolysin C-terminal part gets cleaved off by host cell proteases, it forms a homoheptameric complex. The complex then rapidly forms a β-barrel pore in the plasma membrane. We have used single particle cryo-electron microscopy to obtain the atomic structure of aerolysin variants (mutants) blocked at different stages of the pore formation process Iacovache et al. (2016) Nature communications 7:12062. Our structures revealed that a loop refolds to form of long β-barrel, that a major collapse of the protein leads to membrane insertion of the barrel and, finally, that the cytoplasmic tip of the β-barrel folds outwards to form a rivet within the hydrophobic part of the membrane and thereby firmly anchor the pore in the membrane. Our aim is now to further dissect the mechanism of pore formation to understand in greater details how a water-soluble protein can insert in a membrane bilayer.
Collaborators: Gisou van der Goot (EPFL), Matteo Dal Perraro (EPFL), Nuria Cirauqui (EPFL/Federal University of Rio de Janeiro)
