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Tetanus and botulinum-B neurotoxins block neurotransmitter release by proteolytic cleavage of synaptobrevin

Abstract

CLOSTRIDIAL neurotoxins, including tetanus toxin and the seven serotypes of botulinum toxin (A–G), are produced as single chains and cleaved to generate toxins with two chains joined by a single disulphide bond (Fig. 1). The heavy chain (Mr 100,000 (100K)) is responsible for specific binding to neuronal cells and cell penetration of the light chain (50K), which blocks neurotransmitter release1–9. Several lines of evidence have recently suggested that clostridial neurotoxins could be zinc endopeptidases2,10–14. Here we show that tetanus and botulinum toxins serotype B are zinc endopeptidases, the activation of which requires reduction of the interchain disulphide bond. The protease activity is localized on the light chain and is specific for synaptobrevin, an integral membrane protein of small synaptic vesicles. The rat synaptobrevin-2 isoform is cleaved by both neurotoxins at the same single site, the peptide bond Gln76-Phe77, but the isoform synaptobrevin-1, which has a valine at the corresponding position, is not cleaved. The blocking of neurotransmitter release of Aplysia neurons injected with tetanus toxin or botulinum toxin serotype B is substantially delayed by peptides containing the synaptobrevin-2 cleavage site. These results indicate that tetanus and botulinum B neurotoxins block neurotransmitter release by cleaving synaptobrevin-2, a protein that, on the basis of our results, seems to play a key part in neurotransmitter release.

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References

  1. 1

    Simpson, L. L. (ed.) Botulinum Neurotoxin and Tetanus Toxin (Academic, San Diego, 1989).

  2. 2

    Niemann, H. in (eds Alouf, J. E. & Freer, J. H.) 303–348 A Sourcebook of Bacterial Protein Toxins (Academic, London, 1991).

    Google Scholar 

  3. 3

    Montecucco, C. Trends biochem. Sci. 11, 314–317 (1986).

    CAS  Article  Google Scholar 

  4. 4

    Penner, R., Neher, E. & Dreyer, F. Nature 324, 76–77 (1986).

    ADS  CAS  Article  Google Scholar 

  5. 5

    Gansel, M., Penner, R. & Dreyer, F. Plufgers Arch. 409, 533–539 (1987).

    CAS  Article  Google Scholar 

  6. 6

    Bittner, M. A., DasGupta, B. R. & Holz, R. W. J. biol. Chem. 264, 10354–10360 (1989).

    CAS  PubMed  Google Scholar 

  7. 7

    Molgo, J. et al. J. Physiol., Paris 84, 152–166 (1990).

    CAS  Google Scholar 

  8. 8

    Poulain, B. et al. J. Physiol., Paris 84, 247–261 (1990).

    CAS  Google Scholar 

  9. 9

    Poulain, B. et al. J. biol. Chem. 266, 1–6 (1991).

    Google Scholar 

  10. 10

    Schiavo, G. et al. EMBO J. 11, 3577–3583 (1992).

    CAS  Article  Google Scholar 

  11. 11

    Schiavo, G., Rossetto, O., Santucci, A., DasGupta, B. R. & Montecucco, C. J. biol. Chem. (in the press).

  12. 12

    Vallee, B. L. & Auld, D. S. Biochemistry 29, 5647–5659 (1990).

    CAS  Article  Google Scholar 

  13. 13

    Jongeneel, C. V., Bouvier, J. & Bairoch, A. FEBS Lett. 242, 211–214 (1989).

    CAS  Article  Google Scholar 

  14. 14

    Wright, J. F. et al. J. biol. Chem. 267, 9053–9058 (1992).

    CAS  PubMed  Google Scholar 

  15. 15

    Huttner, W. B., Schiebler, W., Greengard, P. & De Camilli, P. J. Cell Biol. 96, 1374–1378 (1983).

    CAS  Article  Google Scholar 

  16. 16

    Benfenati, F., Bahler, M., Jahn, R. & Greengard, P. J. Cell Biol. 108, 1863–1872 (1989).

    CAS  Article  Google Scholar 

  17. 17

    De Camilli, P. & Jahn, R. A. Rev. Physiol. 52, 625–645.

  18. 18

    Südhof, T. C. & Jahn, R. Neuron 6, 665–677 (1991).

    Article  Google Scholar 

  19. 19

    Trimble, W. S., Linial, M. & Scheller, R. H. A. Rev. Neurosci. 14, 93–122 (1991).

    CAS  Article  Google Scholar 

  20. 20

    Trimble, W. S., Cowan, D. M. & Scheller, R. H. Proc. natn. Acad. Sci. U.S.A. 85, 4538–4542 (1988).

    ADS  CAS  Article  Google Scholar 

  21. 21

    Baumert, M., Maycox, P. R., Navone, F., De Camilli, P. & Jahn, R. EMBO J. 8, 379–384 (1989).

    CAS  Article  Google Scholar 

  22. 22

    Südhof, T. C., Baumert, M., Perin, M. S. & Jahn, R. Neuron 2, 1475–1481 (1989).

    Article  Google Scholar 

  23. 23

    Rappuoli, R. & Pizza, M. G. in A Sourcebook of Bacterial Protein Toxins 1–21 (Academic, London, 1991).

    Google Scholar 

  24. 24

    Hatheway, C. L. Clin. Microbiol. Rev. 3, 66–98 (1990).

    CAS  Article  Google Scholar 

  25. 25

    Koch-Weser, J., Vidt, D. G., Bravo, E. L. & Fauad, F. M. New Engl. J. Med. 306, 214–219 (1982).

    Article  Google Scholar 

  26. 26

    Elferink, L. A., Trimble, W. S. & Scheller, R. H. J. biol. Chem. 264, 11061–11064 (1989).

    CAS  Google Scholar 

  27. 27

    Archer, B. T., Ozcelik, T., Jahn, R., Franke, U. & Südhof, T. C. J. biol. Chem. 265, 17267–17273 (1990).

    CAS  Google Scholar 

  28. 28

    Fontana, A., Dalzoppo, D., Grandi, C. & Zambonin, M. Meth. Enzym. 91, 311–318 (1983).

    CAS  Article  Google Scholar 

  29. 29

    Alder, J., Lu, B., Valtorta, F., Greengard, P. & Poo, M. Science 257, 657–661 (1992).

    ADS  CAS  Article  Google Scholar 

  30. 30

    Brose, N., Petrenko, A. G., Sudhof, T. C. & Jahn, R. Science 256, 1021–1025 (1992).

    ADS  CAS  Article  Google Scholar 

  31. 31

    Schiavo, G., Papini, E., Genna, G. & Montecucco, C. Infect. Immun. 58, 4136–4141 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

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Schiavo, G., Benfenati, F., Poulain, B. et al. Tetanus and botulinum-B neurotoxins block neurotransmitter release by proteolytic cleavage of synaptobrevin. Nature 359, 832–835 (1992). https://doi.org/10.1038/359832a0

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