ON THE ACTION OF BOTULINUM-NEUROTOXIN-A AND BOTULINUM-NEUROTOXIN-E ATCHOLINERGIC TERMINALS

Botulinum neurotoxins type A and E (BoNT/A and /E) are metalloprotease s with a unique specificity for SNAP-25 (synaptosomal-associated prote in of 25 kDa), an essential protein component of the neuroexocytotic m achinery. It was proposed that this specificity is based on the recogn ition of a nine-residue sequence, termed SNARE motif, which is common to the other two SNARE proteins: VAMP (vesicle-associated membrane pro tein) and syntaxin, the only known substrates of the other six clostri dial neurotoxins. Here we report on recent studies which provide evide nce for the involvement of the SNARE motif present in SNAP-25 in its i nteraction with BoNT/A and IE by following the kinetics of proteolysis of SNAP-25 mutants deleted of SNARE motifs. We show that a single cop y of the motif is sufficient for BoNT/A and /E to recognise SNAP-25. W hile the copy of the motif proximal to the cleavage site is clearly in volved in recognition, in its absence, other more distant copies of th e motif are able to support proteolysis. We also report on studies of poisoning human neuromuscular junctions with either BoNT/A or BoNT/E a nd describe the unexpected finding that the time of recovery of functi on after poisoning is much shorter in the case of type E with respect to type A intoxication. These data are discussed in terms of the diffe rent sites of action of the two toxins within SNAP-25. ((C) Elsevier, Paris).