Abstract
The exceptional toxicity of botulinum neurotoxins (BoNTs) is mediated by high avidity binding to complex polysialogangliosides and intraluminal segments of synaptic vesicle proteins embedded in the presynaptic membrane. One peculiarity is an exposed hydrophobic loop in the toxin’s cell binding domain HC, which is located between the ganglioside- and protein receptor-binding sites, and that is particularly pronounced in the serotypes BoNT/B, DC, and G sharing synaptotagmin as protein receptor. Here, we provide evidence that this HC loop is a critical component of their tripartite receptor recognition complex. Binding to nanodisc-embedded receptors and toxicity were virtually abolished in BoNT mutants lacking residues at the tip of the HC loop. Surface plasmon resonance experiments revealed that only insertion of the HC loop into the lipid-bilayer compensates for the entropic penalty inflicted by the dual-receptor binding. Our results represent a new paradigm of how BoNT/B, DC, and G employ ternary interactions with a protein, ganglioside, and lipids to mediate their extraordinary neurotoxicity.
Highlights
Botulinum neurotoxins (BoNTs) are the most toxic bacterial toxins known and are produced e.g. in food by the anaerobic, spore-forming bacteria Clostridium (C.) botulinum, C. butyricum, and C. baratii
Botulinum neurotoxins are Janus-faced molecules: due to their exquisite toxicity, botulinum neurotoxins are considered as biological weapons, but they are highly effective medicines for numerous neurological indications
The neurospecific binding is ensured by anchoring to two receptor molecules both embedded in the membrane: a complex ganglioside and a synaptic vesicle protein
Summary
Botulinum neurotoxins (BoNTs) are the most toxic bacterial toxins known and are produced e.g. in food by the anaerobic, spore-forming bacteria Clostridium (C.) botulinum, C. butyricum, and C. baratii. The resulting flaccid paralysis called botulism can lead to death by respiratory failure [1] Due to their extraordinary toxicity (intraperitoneal median lethal dose (LD50): 1 ng/kg [2]), BoNTs are regarded as a potential biothreat agent [3]. The BoNTs are successfully exploited as pharmacological agents for a broad range of medical and cosmetic applications [4]. Both their potency and specificity can be attributed to an elaborate and elegant mode of action, mediated by the different domains of the 150 kDa molecule [5]. Seven established BoNT serotypes (BoNT/A-G) and the newly pronounced BoNT/HA [aka BoNT/H or BoNT/ FA], BoNT/X, and eBoNT/J [aka BoNT/En]) with more than 40 subtypes have been described which differ by the usage of their specific receptors, their substrate recognition, and/or specific cleavage site targeted [6,7,8,9]
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