Mechanism of membrane translocation by anthrax toxin: insertion and pore formation by protective antigen

Proteolytic activation of receptor-bound protective antigen (PA) at the cell surface removes PA20, allowing PA63 to oligomerize and form a ring-shaped heptameric prepore. The prepore binds edema factor (EF) and lethal factor (LF) and, after endocytosis and trafficking of the complex to an acidic, vesicular compartment, it undergoes membrane insertion and mediates translocation of EF/LF to the cytosol. Data from membrane conductance experiments support a model of membrane insertion in which the 2beta2-2beta3 loop of PA, which is disordered in native PA and the prepore, forms a 14-stranded transmembrane beta-barrel. Recent studies on the process of prepore-to-pore conversion and our current understanding of the mechanism of pH-dependent translocation will be described.