Membrane translocation by anthrax toxin.
Much attention has been focused on anthrax toxin recently, both because of its central role in the pathogenesis of Bacillus anthracis and because it has proven to be one of the most tractable toxins for studying how enzymic moieties of intracellularly acting toxins traverse membranes. The Protective Antigen (PA) moiety of the toxin, after being proteolytically activated at the cell surface, self-associates to form a heptameric pore precursor (prepore). The prepore binds up to three molecules of Edema Factor (EF), Lethal Factor (LF), or both, forming a series of complexes that are then endocytosed. Under the influence of acidic pH within the endosome, the prepore undergoes a conformational transition to a mushroom-shaped pore, with a globular cap and 100A-long stem that spans the membrane. Electrophysiological studies in planar bilayers indicate that EF and LF translocate through the pore in unfolded form and in the N- to C-terminal direction. The pore serves as an active transporter, which translocates its proteinaceous cargo across the endosomal membrane in response to DeltapH and perhaps, to a degree, Deltapsi. A ring of seven Phe residues (Phe427) in the lumen of the pore forms a seal around the translocating polypeptide and blocks the passage of ions, presumably preserving the pH gradient. A charge state-dependent Brownian ratchet mechanism has been proposed to explain how the pore translocates EF and LF. This transport mechanism of the pore may function in concert with molecular chaperonins to effect delivery of effector proteins in catalytically active form to the cytosolic compartment of host cells.
Collier
R John
RJ
Department of Microbiology and Molecular Genetics, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, United States. jcollier@hms.harvard.edu
D000818:Animals; D000881:Anthrax / Q000382:microbiology; D000942:Antigens, Bacterial / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D001408:Bacillus anthracis / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity; D001427:Bacterial Toxins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism*; D004705:Endocytosis / Q000502:physiology*; D006863:Hydrogen-Ion Concentration; D008958:Models, Molecular; D009154:Mutation; D010649:Phenylalanine / Q000378:metabolism; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D021122:Protein Subunits / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport / Q000502:physiology*
D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D021122:Protein Subunits; C030325:anthrax toxin; D010649:Phenylalanine