The symptoms of many bacterial diseases are due largely to the actions of toxic proteins released by the bacteria. Diphtheria, anthrax, cholera, and tetanus toxins are well-known examples. We study these proteins primarily to understand the biochemical basis of bacterial disease and to gain insight into how proteins insert into and cross membranes.
The most potent bacterial toxins act by penetrating into mammalian cells and covalently modifying target substrates within the cytosol. We are currently focusing on diphtheria and anthrax toxins, applying genetic, biochemical, and biophysical methods to generate detailed models of each step in toxin action. How these structurally unrelated toxins insert into bilayers under the influence of low endosomal pH and translocate their enzymic moieties to the cytosol represents a problem of major interest.
Knowledge of the structures and actions of toxins has served as the basis for developing novel pharmaceuticals. We have recently devised new approaches to treating anthrax based on knowledge of how the three components of anthrax toxin assemble into toxic complexes at the mammalian cell surface and how they function during translocation across the endosomal membrane.
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