Both the lethal toxin (LT) and edema toxin (ET) of Bacillus anthracis are
binary toxins and each for activity, must be bound to the protective antigen (PA) to
enter and exert toxicity on eukaryotic cells. Eukaryotic cells harbor specific PA
membrane receptors. Proteolytic activation of PA results in the formation of ring shaped
heptamers which form ion-conductive pores in cell membranes with receptors. Each
prepore binds a total of three EF and/or LF peptides competitively, and after
endocytosis and transport of the complex to an acidic, vesicular compartment, it
undergoes membrane insertion and mediates translocation of EF/LF to the macrophage
cytosol where it exerts its cytotoxic effect. The transmembrane pore houses an aromatic
iris or disk that creates a structural bottleneck in the pore, requiring that the LF and EF
peptides unfold in order to be translocated into the cellular cytosol. This restricted site
has been termed the “Φ-clamp” or phenylalanine clamp. The Φ-clamp or hydrophobic
ratchet is thought to grasp hydrophobic sequences as they unfold from the molten
peptide globule to direct the translocating chain through the channel. Treatment of
macrophages with LT has been found to influence the expression of 103 genes. LT is
proteolytic towards MAPKKs and thereby disrupts intracellular signaling.
Keywords: Lethal toxin, LT, edema toxin, ET, transmembrane pore, protective
antigen, PA, anthrax toxin receptor, ATR, heptamers, ratchet, MAP kinase
kinases, MAPKKs, Macrophages, oxidative burst, apoptosis, autophagy,
proteasome activity, cyclic AMP, cAMP.