The anthrax toxin channel: a barrel of LFs

The use of anthrax as a model system dates back to the late 19th century and Koch's initial investigations into the transmission of infectious diseases (Koch, 1877). These studies, coupled with his subsequent investigations into tuberculosis, enabled Koch to formulate the first set of rules that were used to determine the etiology of a human infectious disease. Koch's postulates, as these rules came to be known, have been used successfully by generations of microbe hunters, and have secured a special place for anthrax in the history of medicine. Anthrax continues to serve as a useful model system, with studies of anthrax toxin, the causative agent of anthrax, yielding insights into bacterial pathogenesis and transport of proteins across membranes (Collier, 2009). It is this last topic—protein translocation—that is the focus of the paper by Basilio et al. in this issue. In particular, the authors address the following question: must the lethal factor (LF) component of anthrax toxin shed all of its secondary structure as it tunnels through the channel formed by the protective antigen (PA) component, or can it retain most of its -helical nature? Because the usual JGP reader is likely less familiar with anthrax toxin channels than with the typical panoply of voltage-gated channels in excitable tissue, it will be helpful to first review some features of this system before delving into the experiments that address the transloca-tion question. Anthrax infection results from exposure to Bacillus anthracis, a gram-positive spore-forming bacterium that is found in soil and in the hair or hides of contaminated animals (Collier and Young, 2003). Although isolated skin contact typically causes only a localized infection in humans, inhalation of aerosolized spores can lead to a hemorrhagic invasive lung disease that is often fatal (Meselson et al., 1994). Cellular injury and death result from the action of anthrax toxin, a tripartite toxin composed of a pore-forming subunit called protective anti-gen (PA), so-named because of its use in generating vaccines, and two distinct enzymatically active subunits: Pathogenesis relies on receptor-mediated endocyto-sis, vesicular acidification, pore formation in the endo-somal membrane by a PA-derived oligomer, and eventual translocation of EF and LF through this pore into the cytosol (Young and Collier, 2007). Once there, LF acts as a zinc-dependent protease that disrupts cellular signal-ing by cleaving proteins of the mitogen-activated protein kinase kinase family (Duesbery et al., 1998), and EF is a calcium-and calmodulin-dependent adenylate cyclase that induces high …