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Letters to Nature
Nature 359, 832 - 835 (29 October 1992); doi:10.1038/359832a0

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

Giampietro G. Schiavo*, Fabio Benfenati, Bernard Poulain, Ornella Rossetto*, Patrizia Polverino de Laureto§, Bibhuti R. DasGupta & Cesare Montecucco*

*Dipartimento di Scienze Biomediche, Centre C.N.R. Biomembrane, and §CRIBI, Università di Padova, 75 Via Trieste, 35121 Padova, Italy
Istituto di Fisiologia Umana, Università di Modena, 41100 Modena, Italy
Laboratoire de Neurobiologie Molèculaire et Cellulaire du CNRS, 91118 Gif-sur-Yvette, France
Food Research Institute, University of Wisconsin at Madison, Wisconsin 53706, USA

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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