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Structural and Biochemical Characterization of Botulinum Neurotoxin Subtype B2 Binding to Its Receptors
Open AccessArticle

The 25 kDa HCN Domain of Clostridial Neurotoxins Is Indispensable for Their Neurotoxicity

Institut für Toxikologie, Medizinische Hochschule Hannover, 30625 Hannover, Germany
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Toxins 2020, 12(12), 743; https://doi.org/10.3390/toxins12120743
Received: 15 August 2020 / Revised: 13 November 2020 / Accepted: 20 November 2020 / Published: 26 November 2020
The extraordinarily potent clostridial neurotoxins (CNTs) comprise tetanus neurotoxin (TeNT) and the seven established botulinum neurotoxin serotypes (BoNT/A-G). They are composed of four structurally independent domains: the roles of the catalytically active light chain, the translocation domain HN, and the C-terminal receptor binding domain HCC are largely resolved, but that of the HCN domain sandwiched between HN and HCC has remained unclear. Here, mutants of BoNT/A, BoNT/B, and TeNT were generated by deleting their HCN domains or swapping HCN domains between each other. Both deletion and replacement of TeNT HCN domain by HCNA and HCNB reduced the biological activity similarly, by ~95%, whereas BoNT/A and B deletion mutants displayed >500-fold reduced activity in the mouse phrenic nerve hemidiaphragm assay. Swapping HCN domains between BoNT/A and B hardly impaired their biological activity, but substitution with HCNT did. Binding assays revealed that in the absence of HCN, not all receptor binding sites are equally well accessible. In conclusion, the presence of HCN is vital for CNTs to exert their neurotoxicity. Although structurally similar, the HCN domain of TeNT cannot equally substitute those of BoNT and vice versa, leaving the possibility that HCNT plays a different role in the intoxication mechanism of TeNT. View Full-Text
Keywords: botulinum neurotoxin; BoNT/A; BoNT/B; tetanus neurotoxin; HCN domain; synaptic vesicle protein; gangliosides botulinum neurotoxin; BoNT/A; BoNT/B; tetanus neurotoxin; HCN domain; synaptic vesicle protein; gangliosides
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MDPI and ACS Style

Deppe, J.; Weisemann, J.; Mahrhold, S.; Rummel, A. The 25 kDa HCN Domain of Clostridial Neurotoxins Is Indispensable for Their Neurotoxicity. Toxins 2020, 12, 743. https://doi.org/10.3390/toxins12120743

AMA Style

Deppe J, Weisemann J, Mahrhold S, Rummel A. The 25 kDa HCN Domain of Clostridial Neurotoxins Is Indispensable for Their Neurotoxicity. Toxins. 2020; 12(12):743. https://doi.org/10.3390/toxins12120743

Chicago/Turabian Style

Deppe, Julian; Weisemann, Jasmin; Mahrhold, Stefan; Rummel, Andreas. 2020. "The 25 kDa HCN Domain of Clostridial Neurotoxins Is Indispensable for Their Neurotoxicity" Toxins 12, no. 12: 743. https://doi.org/10.3390/toxins12120743

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