Binding of botulinum neurotoxins to the luminal surface of synaptic vesicles exposed to medium on neuroexocytosis. The illustration depicts the combined role of polysialogangliosides (purple) and a synaptic vesicle (SV) protein (SV2 or synaptotagmin; orange) in mediating botulinum neurotoxin (BoNT)-neurospecific binding and entry into neurons after the retrieval of the vesicle. It suggests additional low-affinity interactions with other molecules (lipids and/or proteins) of the SV membrane (green; modified from Montecucco et al, 2004). Multiple interactions with molecules of the SV membrane would allow almost irreversible neuron binding, which would then become completely irreversible on vesicle fission from the presynaptic membrane. The yellow and grey areas denote the different compositions of the SV and presynaptic membranes, respectively. H, heavy chain of BoNT; L, light chain of BoNT; VAMP, vesicle-associated membrane protein.