Dissecting the L Chains of Clostridial Neurotoxins
Tetanus toxin (TeTx) and the seven structurally related but serologically distinct botulinal neurotoxins, designated BoNT/A to BoNT/G, bind selectively to nerve terminals where they are internalized and sorted by unknown mechanisms. It is generally accepted that toxification is preceeded by a translocation of the L chains from an acid vesicular environment into the cytosole (Niemann, 1991). Despite such homologies, however, the individual toxins display differences in their primary sites of action, their uptake mechanisms (Poulain et al., 1992) and sensitivity to chemical antagonists (Dreyer et al., 1987; Dolly et al., 1990). We have to assume, therefore, that some of the neurotoxins act on different intracellular targets which appear to play key roles in neurotransmitter release from small translucent as well as large dense-core vesicles. Although tetanus patients immediately receive high doses of human tetanus immune globulin to block any nonbound toxin, the internalized toxin evokes its toxic effects for several weeks (Bleck, 1989). This suggests that the toxins act as enzymes. Several enzymatic activities have been proposed over the past years all of which, however, proved to be wrong later on (Niemann, 1991).
KeywordsBotulinal Toxin Botulinum Neurotoxin Tetanus Toxin Clostridium Botulinum Isoelectric Focussing
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- Bleck, T.P., 1989, Clinical aspects of tetanus, in: Botulinum Neurotoxin and Tetanus Toxin, L.L. Simpson, ed., Academic Press, San Diego.Google Scholar
- Dolly, J.O., Ashton, A.C., McInnes, C., Wadsworth, J.D.F. Poulain, B., Tauc, L., Shone, C.C., and Melling, J., 1990, Clues to the multiphase inhibitory action of botulinum neurotoxins on release of transmitters, J. Physiol. (Paris) 84: 237.Google Scholar
- Dreyer, F., Rosenberg, F., Becker, C., Bigalke, H.,and Penner, R., 1987, Differential effects of various secretagogues on quantal transmitter release from mouse nerve terminals treated with botulinum A and tetanus toxin. Naunyn Schmiedeberg’s Arch. of Pharmacol. 335: 1.Google Scholar
- Eisel, U., Jarausch, W., Goretzki, K., Henschen, A., Engels, J., Weller, U., Hudel, M., Habermann, E., and Niemann, H., 1986, Tetanus toxin: primary structure, expression in E. coli, and homology with botulinum toxins, EMBO J. 5: 2495.Google Scholar
- Kurazono, H., Mochida, S., Binz, T., Eisel, U., Quanz, M., Grebenstein, O., Poulain, B., Tauc, L., and Niemann, H., 1992a, Minimal essential domains specifying toxicity of the light chains of tetanus toxin and botulinum neurotoxin type A, J. Biol. Chem.,in press.Google Scholar
- Kurazono, S., Kozaki, S., Binz, T., Grebenstein, O., and Niemann, H., 1992b, Monoclonal antibodies as tools to dissect the L chains of clostridial neurotoxins, manuscript n preparation.Google Scholar
- Niemann, H., 1991, Molecular biology of clostridial neurotoxins. in: Sourcebook of Bacterial Protein Toxins, Alouf, J. and Freer, J. eds., pp 303–348. Academic Press, New York.Google Scholar
- Poulain, B., Tauc, L.,Maisey, E.A., Wadsworth, J.D:F., Mohan, P.M., and Dolly, J.O., 1988, Neurotransmitter release is blocked intracellularly by botulinum toxin, and this requires both polypeptides by a process mediated by the larger chain. Proc. Natl. Acad. Sci. USA 85: 4090.Google Scholar
- Poulain, B., Wadsworth, J.D.F., Shone, C.C., Mochida, S., Lande, S., Melling, J., Dolly, J.O., and Tauc, L., 1989, Multiple domains of botulinum neurotoxin contribute to its inhibition of transmitter release in Aplysia neurons, J. Biol. Chem. 264: 2 1928.Google Scholar
- Poulet, S., Hauser, D., Quanz, M., Niemann, H., and Popoff, M.R., 1992, Sequences of the botulinal neurotoxin E derived from Clostridium botulinum type E (strain Beluga) and Clostridium butyricum (strains ATCC43181 and ATCC43755). Biochem. Biophys. Res. Commun. 183: 107.Google Scholar