Botulinum neurotoxins serotypes A and E cleave SNAP‐25 at distinct COOH‐terminal peptide bonds

SNAP‐25, a membrane‐associated protein of the nerve terminal, is specifically cleaved by botulinum neurotoxins serotypes A and E, which cause human and animal botulism by blocking neurotransmitter release at the neuromuscular junction. Here we show that these two metallo‐endopeptidase toxins cleave SNAP‐25 at two distinct carboxyl‐terminal sites. Serotype A catalyses the hydrolysis of the Gln 197 ‐Arg 198 peptide bond, while serotype E cleaves the Arg 180 ‐Ile 181 peptide linkage. These results indicate that the carboxyl‐terminal region of SNAP‐25 plays a crucial role in the multi‐protein complex that mediates vesicle docking and fusion at the nerve terminal.