Abstract
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.
Highlights
The family of clostridial neurotoxins (CNTs) consists of tetanus neurotoxin (TeNT), the seven established botulinum neurotoxin serotypes (BoNT/A-G), and the recently identified novel typesbotulinum neurotoxins (BoNTs)/HA, BoNT/X, and eBoNT/J from Enterococcus [1,2,3,4]
ProteinsProteins of similar but size different folding, folding, which could act as a rigid spacer, cannot adopt that role
The HCN A is defined from K871-N1093, HCN B covers S858-Y1080, and HCN T spans from
Summary
The family of clostridial neurotoxins (CNTs) consists of tetanus neurotoxin (TeNT), the seven established botulinum neurotoxin serotypes (BoNT/A-G), and the recently identified novel typesBoNT/HA (aka H & FA), BoNT/X, and eBoNT/J (aka BoNT/En) from Enterococcus [1,2,3,4]. The family of clostridial neurotoxins (CNTs) consists of tetanus neurotoxin (TeNT), the seven established botulinum neurotoxin serotypes (BoNT/A-G), and the recently identified novel types. The insecticidal neurotoxin PMP1 isolated from a Paraclostridium bifermentans strain has been identified as a structural homologue of CNTs [5]. Botulinum neurotoxins (BoNTs) are produced by the bacteria Clostridium botulinum and are the most poisonous protein toxins known [6]. They cause the disease botulism by blocking release of acetylcholine at the neuromuscular junction, resulting in muscle relaxation. TeNT is toxic, but blocks the release of glycine and GABA at inhibitory neurons, resulting in spastic paralysis and the disease tetanus
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