Botulinum neurotoxins: A distinct subclass of SNARE-Cleaving endopeptidases

Botulinum neurotoxins (BoNTs) are bacterial protein toxins that cause the severe and potentially fatal neuro-paralytic disease botulism in humans and vertebrate animals. Together with tetanus toxin (TeNT), BoNTs comprise the large family of clostridial neurotoxins (CNTs). Structurally, CNTs share conserved features: a 50 kDa zinc-dependent light chain endopeptidase with an HExxH motif linked via a disulfide bond to a 100 kDa heavy chain with distinct domains for translocation and receptor binding that mediate neuronal specificity. During the last decade, genomic analyses have uncovered bont-like genes in non-clostridial species including as Weissella oryzae, Enterococcus faecium, Paeniclostridium ghonii, Chryseobacterium piperi, Paraclostridium bifermentans, and Bacillustoyonensis. The BoNT-like proteins encoded by these genes retain SNARE-cleaving activity and share structural motifs with BoNTs, yet studies during the last decade have shown they exhibit minimal toxicity in vertebrate systems and form phylogenetically distinct clades, suggesting alternative ecological roles. Growing evidence suggests insects as the target of BoNT-like proteins. The expanding repertoire of BoNT-like proteins with conserved architecture and enzymatic function supports the classification of BoNTs as a distinct sub-family within a broader super-family of SNARE-cleaving endopeptidases. We propose the designation SNACLEs (SNARE-Cleaving-Endopeptidases) for this protein super-family, with CNTs and BoNT-like proteins as a distinct families.