Botulinum and Tetanus Neurotoxins

Abstract

Botulinum neurotoxins (BoNTs) and tetanus neurotoxin (TeNT) are the most potent toxins known and cause botulism and tetanus, respectively. BoNTs are also widely utilized as therapeutic toxins. They contain three functional domains responsible for receptor-binding, membrane translocation, and proteolytic cleavage of host proteins required for synaptic vesicle exocytosis. These toxins also have distinct features: BoNTs exist within a progenitor toxin complex (PTC), which protects the toxin and facilitates its absorption in the gastrointestinal tract, whereas TeNT is uniquely transported retrogradely within motor neurons. Our increasing knowledge of these toxins has allowed the development of engineered toxins for medical uses. The discovery of new BoNTs and BoNT-like proteins provides additional tools to understand the evolution of the toxins and to engineer toxin-based therapeutics. This review summarizes the progress on our understanding of BoNTs and TeNT, focusing on the PTC, receptor recognition, new BoNT-like toxins, and therapeutic toxin engineering.

Tables of Toxicity of Botulinum and Tetanus Neurotoxins

“…The extremely high potency of clostridial neurotoxins is due to the unique combination of two factors: (a) the very rapid binding to neurons, whose integrity is essential for survival, and (b) their enzymatic activity highly specific for the three SNARE proteins, whose cleavage is sufficient to block neurotransmitter release with ensuing neuroparalysis [2,3]. This is evident for vertebrates, but it is also true for invertebrates-particularly for flying insects, as shown by the very recent discovery of a BoNT-like neurotoxin specific for Anopheles mosquitos [92].…”

“…Tetanus and botulinum neurotoxins are produced by different species of anaerobic bacteria of the genus Clostridium [2,3]. They cause the neuroparalytic syndromes of tetanus and botulism in mammals and other vertebrates [4,5].…”

The role of the single interchains disulfide bond in tetanus and botulinum neurotoxins and the development of antitetanus and antibotulism drugs

“…This feature leads to a reorientation of the tumbling BoNT molecule while approaching to the membrane in such a way that almost any hit with the ganglioside results in toxin binding (Fogolari, Tosatto, Muraro, & Montecucco, 2009). BoNT/A and BoNT/E bind to SV2, their protein receptor, whereas BoNT/B, BoNT/G, and BoNT/DC bind to the synaptic vesicle protein synaptotagmin I/II (Binz & Rummel, 2009;Dong et al, 2018). Such a binding is followed by endocytosis inside synaptic vesicle.…”

Characterization of a membrane binding loop leads to engineering botulinum neurotoxin B with improved therapeutic efficacy

“…Botulinum neurotoxins (BoNTs) are a family of protein toxins produced by various clostridial bacteria [1][2][3]. They target motor nerve terminals and block neurotransmitter release, resulting in muscle paralysis.…”

“…BoNTs are approximately 150-kDa proteins composed of a light chain (LC, approximately 50 kDa) and a heavy chain (HC, approximately 100 kDa), connected via a single disulfide bond [2,3,5,6]. The HC includes the N-terminal translocation domain (H N , approximately 50 kDa) and the C-terminal receptor-binding domain (H C , approximately 50 kDa).…”