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Botulinum neurotoxins (BoNT) cause muscle paralysis by inhibiting the exocytosis at motor nerve terminals. Initially, they bind to abundant complex polysialogangliosides via a conserved pocket within the C-terminal half of their cell binding domain (Hcc-domain). Engineering of this binding site in BoNT/A leads to mutants with >3-fold increased potency, which can be exploited as new therapeutics with decreased dosage and thus might prolong the period until immune response in patients. Additionally, protein receptors are required for productive neurotoxin uptake. While BoNT/B and G share the synaptic vesicle proteins synaptotagmin (Syt) I and Syt-II as protein receptors, BoNT/A uniquely binds SV2. Recently, the interaction site of Syt I and Syt-II was located near the ganglioside binding pocket within the Hcc-domain of BoNT/B and G. Furthermore, the BoNT/B–Syt II interaction could be characterised at the atomic level. None of the so-far identified protein receptors interacts with BoNT/C, D, E, F and TeNT. Employing the ex vivo mouse phrenic nerve-hemidiaphragm as a physiological target, the type and number of unknown neurotoxin receptor candidates were narrowed down. The productive uptake of BoNT/C, D, E and F is stimulation dependent, which points towards receptors being part of synaptic vesicles. Moreover, the endocytosis of BoNT/C, E and F, is inhibited by addition of any Hc-fragment derived from BoNT/C, E and F, indicating a binding to the same receptor structures. |
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