Structural basis for the unfolding of anthrax lethal factor by protective antigen oligomers

The protein transporter anthrax lethal toxin is composed of protective antigen (PA), a transmembrane translocase, and lethal factor (LF), a cytotoxic enzyme. After its assembly into holotoxin complexes, PA forms an oligomeric channel that unfolds LF and translocates it into the host cell. We report the crystal structure of the core of a lethal toxin complex to 3.1-angstrom resolution; the structure contains a PA octamer bound to four LF PA-binding domains (LFN). The first a-helix and beta-strand of each LFN unfold and dock into a deep amphipathic cleft on the surface of the PA octamer, which we call the alpha clamp. The alpha clamp possesses nonspecific polypeptide binding activity and is functionally relevant to efficient holotoxin assembly, PA octamer formation, and LF unfolding and translocation. This structure provides insight into the mechanism of translocation-coupled protein unfolding.