A molecular basis underlying differences in the toxicity of botulinum serotypes A and E

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Abstract
Botulinum neurotoxins (BoNTs) block neurotransmitter release through their specific proteolysis of the proteins responsible for vesicle exocytosis. Paradoxically, two serotypes of BoNTs, A and E, cleave the same molecule, synaptosome‐associated protein with relative molecular mass 25K (SNAP‐25), and yet they cause synaptic blockade with very different properties. Here we compared the action of BoNTs A and E on the plasma membrane fusion machinery composed of syntaxin and SNAP‐25. We now show that the BoNT/A‐cleaved SNAP‐25 maintains its association with two syntaxin isoforms in vitro , which is mirrored by retention of SNAP‐25 on the plasma membrane in vivo . In contrast, BoNT/E severely compromises the ability of SNAP‐25 to bind the plasma membrane syntaxin isoforms, leading to dissociation of SNAP‐25. The distinct properties of botulinum intoxication, therefore, can result from the ability of shortened SNAP‐25 to maintain its association with syntaxins—in the case of BoNT/A poisoning resulting in unproductive syntaxin/SNAP‐25 complexes that impede vesicle exocytosis.