Tetanus and botulinum neurotoxins are zinc proteases specific for components of the neuroexocytosis apparatus.
Tetanus and botulinum neurotoxins bind to nerve cells, penetrate the cytosol, and block neurotransmitter release. Comparison of their amino-acid sequences shows the presence of the highly conserved His-Glu-x-x-His zinc-binding motif of zinc-endopeptidases (HExxH). Atomic absorption measurements of clostridial neurotoxins show the presence of one atom of zinc/toxin molecule bound to the light chain. The toxin-bound zinc ion is essential for the neurotoxins inhibition of neurotransmitter release in Aplysia neurons injected with the toxins. Phosphoramidon, a very specific inhibitor of zinc-endopeptidases, blocks the intracellular activity of the clostridial neurotoxins. Highly purified preparations of the light chain of tetanus and botulinum B and F neurotoxins cleaved specifically VAMP/synaptobrevin, an integral membrane protein of small synaptic vesicles, both in vivo and in vitro. From these studies, it can be concluded that the clostridial neurotoxins responsible for tetanus and botulism block neuroexocytosis via the proteolytic cleavage of specific components of the neuroexocytotic machinery.
Schiavo
G
G
Centro C.N.R. Biomembrane, Università di Padova, Italy.
Rossetto
O
O
Benfenati
F
F
Poulain
B
B
Montecucco
C
C
D000595:Amino Acid Sequence; D000818:Animals; D001048:Aplysia; D001665:Binding Sites; D001905:Botulinum Toxins / Q000737:chemistry / Q000633:toxicity*; D002540:Cerebral Cortex / Q000502:physiology; D017124:Conserved Sequence; D005089:Exocytosis / Q000187:drug effects* / Q000502:physiology; D005724:Ganglia / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D008666:Metalloendopeptidases / Q000737:chemistry / Q000633:toxicity*; D008969:Molecular Sequence Data; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D018377:Neurotransmitter Agents / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D013572:Synaptic Vesicles / Q000187:drug effects / Q000502:physiology*; D013744:Tetanus Toxin / Q000737:chemistry / Q000633:toxicity*; D015032:Zinc / Q000032:analysis / Q000378:metabolism*
D018377:Neurotransmitter Agents; D013744:Tetanus Toxin; D008666:Metalloendopeptidases; C093556:zinc-endopeptidase, tetanus neurotoxin; D001905:Botulinum Toxins; D015032:Zinc