Structural determinants of the specificity for synaptic vesicle- associated membrane protein/synaptobrevin of tetanus and botulinum type B and G neurotoxins

Rossella Pellizzari*, Ornella Rossetto, Luisa Lozzi, Silvia Giovedi, Eric Johnson, Clifford Shone, Cesare Montecucco

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

97 Citations (Scopus)

Abstract

Tetanus and botulinum neurotoxins type B and G are zinc-endopeptidases of remarkable specificity. They recognize and cleave a synaptic vesicle- associated membrane protein (VAMP)/synaptobrevin, an essential protein component of the vesicle docking and fusion apparatus. VAMP contains two copies of a nine-residue motif, also present in SNAP-25 (synaptosomal- associated protein of 25 kDa) and syntaxin, the two other substrates of clostridial neurotoxins. This motif was suggested to be a determinant of the target specificity of neurotoxins. Antibodies raised against this motif cross-react among VAMP, SNAP-25, and syntaxin and inhibit the proteolytic activity of the neurotoxins. Moreover, the various neurotoxins cross-inhibit each other's proteolytic action. The role of the three negatively charged residues of the motif in neurotoxin recognition was probed by site-directed mutagenesis. Substitution of acidic residues in both copies of the VAMP motif indicate that the first one is involved in tetanus neurotoxin recognition, whereas the second one is implicated in binding botulinum B and G neurotoxins. These results suggest that the two copies of the motif have a tandem association in the VAMP molecule.

Original languageEnglish
Pages (from-to)20353-20358
Number of pages6
JournalJournal of Biological Chemistry
Volume271
Issue number34
DOIs
Publication statusPublished - 1996

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