UCLA

Pathogenesis of anthrax disease involves two cytotoxic enzymes-edema factor (EF) and lethal factor (LF)-which are individually recruited by the protective antigen heptamer (PA₇) or octamer (PA₈) prechannel and subsequently translocated across channels formed on the endosomal membrane upon exposure to low pH. Here, we report the atomic structures of PA₈ prechannel-bound full-length EF and LF. In this pretranslocation state, the N-terminal segment of both factors refolds into an α helix engaged in the α clamp of the prechannel. Recruitment to the PA prechannel exposes an originally buried β strand of both toxins and enables domain organization of EF. Many interactions occur on domain interfaces in both PA prechannel-bound EF and LF, leading to toxin compaction prior to translocation. Our results provide key insights into the molecular mechanisms of translocation-coupled protein unfolding and translocation.