ABSTRACT
Tetanus and botulinum neurotoxins are produced by anaerobic bacteria of the genus Clostridium and cause the paralytic syndromes of tetanus and botulism. They are synthesized as a single inactive 150 kDa polypeptide chain and activated by specific proteolysis with the generation of two disulphide-linked polypeptides, termed H and L. The larger chain H is responsible for neurospecific binding and cell penetration. Reduction releases the L chain in the neuronal cytosol, where it displays its catalytic activity. The L chain is a zinc endopeptidase specific for protein components of the neuroexocytosis apparatus. Tetanus neurotoxin and botulinum neurotoxin serotypes B, D, F and G recognize specifically VAMP/synaptobrevin, an integral membrane protein of the synaptic vesicles. Botulinum A and E neurotoxins recognize and cleave specifically SNAP-25, a protein of the presynaptic membrane, whereas serotype C cleaves specifically syntaxin, another protein of the nerve plasmalemma. These three protein targets are cleaved at single sites, which differ for each neurotoxin. The fact that neurotoxins that cause a persistent blockade of neuroexocytosis attack VAMP, SNAP-25 and syntaxin indicates that these three proteins play an important role in the process. The unique sequence, mechanism of activation and target specificity of tetanus and botulinum neurotoxins individualize them as an independent group of zinc endopeptidases.
