Structure of anthrax lethal toxin prepore complex suggests a pathway for efficient cell entry

Abstract

Anthrax toxin is a tripartite complex in which the protective antigen moiety forms a pore through which lethal factor and edema factor are translocated. Fabre et al. reveal a mechanism for efficient translocation in their structure of the heptameric protective antigen prepore bound to three lethal factors.

Abstract

Anthrax toxin comprises three soluble proteins: protective antigen (PA), lethal factor (LF), and edema factor (EF). PA must be cleaved by host proteases before it oligomerizes and forms a prepore, to which LF and EF bind. After endocytosis of this tripartite complex, the prepore transforms into a narrow transmembrane pore that delivers unfolded LF and EF into the host cytosol. Here, we find that translocation of multiple 90-kD LF molecules is rapid and efficient. To probe the molecular basis of this translocation, we calculated a three-dimensional map of the fully loaded (PA ₆₃) ₇–(LF) ₃ prepore complex by cryo–electron microscopy (cryo-EM). The map shows three LFs bound in a similar way to one another, via their N-terminal domains, to the surface of the PA heptamer. The model also reveals contacts between the N- and C-terminal domains of adjacent LF molecules. We propose that this molecular arrangement plays an important role in the maintenance of translocation efficiency through the narrow PA pore.