Presynaptic receptor arrays for clostridial neurotoxins

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Tetanus and botulinum neurotoxins act at femtomolar concentrations and are specific for the presynaptic membrane of neurons. Their mode of binding is still poorly defined. The exceptional potency and specificity of these neurotoxins raise unprecedented questions about the nature of their receptor(s) and the mode of their membrane binding. We propose a presynaptic binding process for tetanus and botulinum neurotoxins based on a capture step performed by an antenna, consisting of a lipid- or a protein-linked oligosaccharide, which brings about a very large membrane concentration effect; this is followed by additional interactions with arrays of receptor molecules, arranged in membrane microdomains, which render the neurotoxin binding practically irreversible and triggers endocytosis.