LAUSR

Following assembly, the anthrax protective antigen (PA) forms an oligomeric translocon that unfolds and translocates either its lethal factor (LF) or edema factor (EF) into the host cell. Here, we report the cryo-EM structures of heptameric PA channels with partially unfolded LF and EF at 4.6 and 3.1-Å resolution, respectively. The first α helix and β strand of LF and EF unfold and dock into a deep amphipathic cleft, called the α clamp, which resides at the interface of two PA monomers. The α-clamp-helix interactions exhibit structural plasticity when comparing the structures of lethal and edema toxins. EF undergoes a largescale conformational rearrangement when forming the complex with the channel. A critical loop in the PA binding interface is displaced for about 4 Å, leading to the weakening of the binding interface prior to translocation. These structures provide key insights into the molecular mechanisms of translocation-coupled protein unfolding and translocation. The bacterial translocase channel anthrax toxin is composed of the protective antigen (PA) that forms a translocase channel and two cytotoxic enzymes: lethal factor (LF) and edema factor (EF), which go through the PA channel to enter host cells. Here the authors provide mechanistic insights into LF and EF translocation by determining the cryo-EM structures of the anthrax toxin transmembrane channel protein in complex with LF and EF.