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Clostridial Toxins in a new light
Autocatalytic cleavage activates toxin B from Clostridium difficile
Diarrhea through to pseudomembranous colitis are often the complications associated with antibiotic therapy. The reason behind this is that the antibiotic brings the natural intestinal bacteria out of balance, therefore allowing damaging bacteria like C. difficile to take over.
These bacteria produce toxic proteins which are composed of long polypeptide chains that have a tripartite functional structure: the carboxy-terminal domain is responsible for binding to the host cell membrane; the hydrophobic middle part is supposed to be involved in translocation across cellular membranes; and the amino-terminal domain harbors the enzyme that is responsible for the damaging effects. By cleavage of the toxin, the enzyme is released and activated.
Until recently, it was assumed that an aspartic protease in the host cell caused the cleavage of the toxins. Dr. Christoph von Eichel-Streiber, the University of Mainz and owners of Mainz tgcBIOMICS worked together and refuted this hypothesis. They proved that an autocatalytic process for the cleavage of toxin B out of C. difficile exists [Nature 2007, 446, 415-419].
Toxin B binds to a host cell receptor and is endocytosed into the host cell. The low pH in the endosome triggers the conformational change of the polypeptide chain. Thereafter, the hydrophobic domain of the toxin goes through the membrane and pushes the catalytic domain into the cytosol. There the cellular inositolphosphate connects to the toxin and activates over a further conformational change the intrinsic protease.
The autocatalytic cleavage of the protein releases the active glycosyltransferase out of the toxin into the cytosol, which then glycosylated the GTPases of the Rho/Rac family (small GTP binding proteins which aid in the construction of cytoskeleton), leading to a blockade of signal transduction processes. Consequently, this leads to disaggregation of the cytoskeleton and cell death.