The pore of the matter

PLoS Pathog. 7, e1002354 (2011)

Credit: PUBLIC LIBRARY OF SCIENCE

The entry of anthrax toxin into host cells after Bacillus anthracis infection follows a series of well-known steps, from binding of the 83-kDa toxin (PA₈₃) to cellular receptors such as ANTXR2 and cleavage to and heptamerization of a 63-kDa form (PA₆₃) that forms a 'prepore' structure, to formation of a PA₆₃ pore within acidic compartments that allow the toxin to escape into the host cytosol. It is thought that binding of the toxin to the VWA domain of ANTXR2 hinders movements that are necessary for pore formation; once this interaction is released by the low pH of internal compartments, the pore can readily form. To learn more about the PA-receptor interaction, such as whether the complex dissociates within cells, Pilpa et al. used the NMR transfer cross-saturation method, which can be used to identify the binding interface of large protein-protein complexes. The data comparing contacts at pH 5.1, 6.0 and 8.0 suggest a model in which the receptor remains bound to domain 4 of PA but loses its interactions with PA domain 2 prior to prepore-to-pore conversion. The partially bound receptor may act to stabilize the toxin heptameric structure. They also reveal a new toxin-receptor intermediate, which possibly exists in the mildly acidic early endosome, on the path to pore formation.