Structure and Function of Clostridial and Botulinum-Like Neurotoxins

A special issue of Toxins (ISSN 2072-6651). This special issue belongs to the section "Bacterial Toxins".

Deadline for manuscript submissions: closed (15 December 2021) | Viewed by 20240

Special Issue Editor


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Guest Editor
Department of Pharmacy and Pharmacology, and Centre for Therapeutic Innovation, University of Bath, Bath, UK

Special Issue Information

Dear Colleagues,

Members of the clostridial neurotoxins are the most poisonous protein toxins known to man, and the causative agents of the potentially fatal diseases tetanus and botulism. This family of potent toxins has recently witnessed rapid expansion beyond the tetanus toxin (TeNT) and seven serotypes and over forty subtypes that have classically defined the botulinum neurotoxins (BoNTs). This includes potential novel BoNT serotypes and natural chimeric proteins with mixed types whose biochemical and pharmacological properties are being investigated. In addition, with advances in high-throughput genomics technology, environmental samples have revealed new BoNT-like proteins, particularly in non-clostridial bacterial species. Determining the function and potency of these new toxins is essential to ensuring they do not pose any biological threats in addition to assessing their potential for biotechnological use. Whilst the main function of BoNTs is well defined, as they specifically target neuromuscular junctions resulting in inhibition of neurotransmission and causing paralysis, the species selectivity and effect of new toxins on their target―which is unknown in some cases―is not evident. Determining the structure and activity of these toxins and homologues will provide important information to understanding their evolution, and how they have developed specific host interactions. It will also provide a basis for the development of novel biotechnological tools that can extend how this family of toxins can be used beyond the current BoNT therapeutic applications.

This Special Issue “Structure and Function of Clostridial and Botulinum-Like Neurotoxins” aims to bring together the latest research on the biochemical properties and function of BoNTs, their newly identified homologues, and of proteins associated with their toxicity.

Dr. Geoffrey Masuyer
Guest Editor

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Keywords

  • botulinum
  • neurotoxins
  • clostridial toxins
  • bacterial toxins
  • protein engineering
  • protein structure
  • biotechnology

Published Papers (6 papers)

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Research

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18 pages, 3672 KiB  
Article
Botulinum Neurotoxin Type A Directly Affects Sebocytes and Modulates Oleic Acid-Induced Lipogenesis
by Karen Brami-Cherrier, Alex Chernavsky, Hui You, Sergei A. Grando, Amy Brideau-Andersen and Birgitte Sondergaard
Toxins 2022, 14(10), 708; https://doi.org/10.3390/toxins14100708 - 15 Oct 2022
Cited by 3 | Viewed by 3565
Abstract
Excess sebum (seborrhea) results in oily skin and is associated with large pore size and acne. Studies in healthy, seborrheic volunteers have reported that intradermal injection of commercial preparations of botulinum neurotoxin type A (BoNT/A) (onabotulinumtoxinA, abobotulinumtoxinA, and incobotulinumtoxinA) reduced sebum production, and [...] Read more.
Excess sebum (seborrhea) results in oily skin and is associated with large pore size and acne. Studies in healthy, seborrheic volunteers have reported that intradermal injection of commercial preparations of botulinum neurotoxin type A (BoNT/A) (onabotulinumtoxinA, abobotulinumtoxinA, and incobotulinumtoxinA) reduced sebum production, and thus, skin oiliness and pore size. The mechanism for these effects has not been fully elucidated; however, several theories involving direct or indirect effects of BoNT/A on neuronal and/or dermal cells (e.g., sebocytes) have been proposed. In the present study, we evaluated the direct effect of native research grade BoNT/A complex, a commercial preparation of BoNT/A (onabotA), and BoNT/A variants on sebocyte lipogenesis using an in vitro sebocyte cell model. We show that picomolar concentrations of BoNT/A (BoNT/A complex: half maximal effective concentration [EC50] = 24 pM; BoNT/A 150 kDa: EC50 = 34 pM) modulate sebocyte lipogenesis and reduce oleic acid-induced sebocyte differentiation, lipogenesis, and holocrine-like secretion. Comparative studies with the binding domain of BoNT/A, which lacks enzymatic activity, show that this effect is independent of the enzymatic activity of BoNT/A and likely occurs via sebocyte cell surface receptors (e.g., fibroblast growth factor receptors). Overall, these results shed light on the potential mechanism of action and rationale for use of BoNT/A for treatment of sebum-related conditions. Full article
(This article belongs to the Special Issue Structure and Function of Clostridial and Botulinum-Like Neurotoxins)
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17 pages, 2843 KiB  
Article
The Isolated Mouse Jejunal Afferent Nerve Assay as a Tool to Assess the Effect of Botulinum Neurotoxins in Visceral Nociception
by Kevin Retailleau, Vincent Martin, Stephane Lezmi, Camille Nicoleau and Jacquie Maignel
Toxins 2022, 14(3), 205; https://doi.org/10.3390/toxins14030205 - 11 Mar 2022
Cited by 2 | Viewed by 2216
Abstract
For the past two decades, botulinum neurotoxin A (BoNT/A) has been described as a strong candidate in the treatment of pain. With the production of modified toxins and the potential new applications at the visceral level, there is a real need for tools [...] Read more.
For the past two decades, botulinum neurotoxin A (BoNT/A) has been described as a strong candidate in the treatment of pain. With the production of modified toxins and the potential new applications at the visceral level, there is a real need for tools allowing the assessment of these compounds. In this study, we evaluated the jejunal mesenteric afferent nerve assay to investigate BoNT/A effects on visceral nociception. This ex vivo model allowed the continuous recording of neuronal activity in response to various stimuli. BoNT/A was applied intraluminally during three successive distensions, and the jejunum was distended every 15 min for 3 h. Finally, samples were exposed to external capsaicin. BoNT/A intoxication was validated at the molecular level with the presence of cleaved synaptosomal-associated protein of 25 (SNAP25) in nerve terminals in the mucosa and musculosa layers 3 h after treatment. BoNT/A had a progressive inhibitory effect on multiunit discharge frequency induced by jejunal distension, with a significant decrease from 1 h after application without change in jejunal compliance. The capsaicin-induced discharge was also affected by the toxin. This assay allowed the description of an inhibitory effect of BoNT/A on afferent nerve activity in response to distension and capsaicin, suggesting BoNT/A could alleviate visceral nociception. Full article
(This article belongs to the Special Issue Structure and Function of Clostridial and Botulinum-Like Neurotoxins)
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12 pages, 3518 KiB  
Article
Crystal Structures of Botulinum Neurotoxin Subtypes A4 and A5 Cell Binding Domains in Complex with Receptor Ganglioside
by Kyle S. Gregory, Otsile O. Mojanaga, Sai Man Liu and K. Ravi Acharya
Toxins 2022, 14(2), 129; https://doi.org/10.3390/toxins14020129 - 8 Feb 2022
Cited by 5 | Viewed by 3909
Abstract
Botulinum neurotoxins (BoNT) cause the potentially fatal neuroparalytic disease botulism that arises due to proteolysis of a SNARE protein. Each BoNT is comprised of three domains: a cell binding domain (HC), a translocation domain (HN), and a catalytic (Zn [...] Read more.
Botulinum neurotoxins (BoNT) cause the potentially fatal neuroparalytic disease botulism that arises due to proteolysis of a SNARE protein. Each BoNT is comprised of three domains: a cell binding domain (HC), a translocation domain (HN), and a catalytic (Zn2+ endopeptidase) domain (LC). The HC is responsible for neuronal specificity by targeting both a protein and ganglioside receptor at the neuromuscular junction. Although highly toxic, some BoNTs are commercially available as therapeutics for the treatment of a range of neuromuscular conditions. Here we present the crystal structures of two BoNT cell binding domains, HC/A4 and HC/A5, in a complex with the oligosaccharide of ganglioside, GD1a and GM1b, respectively. These structures, along with a detailed comparison with the previously reported apo-structures, reveal the conformational changes that occur upon ganglioside binding and the interactions involved. Full article
(This article belongs to the Special Issue Structure and Function of Clostridial and Botulinum-Like Neurotoxins)
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13 pages, 3718 KiB  
Article
Structural Analysis of Botulinum Neurotoxins Type B and E by Cryo-EM
by Sara Košenina, Markel Martínez-Carranza, Jonathan R. Davies, Geoffrey Masuyer and Pål Stenmark
Toxins 2022, 14(1), 14; https://doi.org/10.3390/toxins14010014 - 23 Dec 2021
Cited by 3 | Viewed by 3979
Abstract
Botulinum neurotoxins (BoNTs) are the causative agents of a potentially lethal paralytic disease targeting cholinergic nerve terminals. Multiple BoNT serotypes exist, with types A, B and E being the main cause of human botulism. Their extreme toxicity has been exploited for cosmetic and [...] Read more.
Botulinum neurotoxins (BoNTs) are the causative agents of a potentially lethal paralytic disease targeting cholinergic nerve terminals. Multiple BoNT serotypes exist, with types A, B and E being the main cause of human botulism. Their extreme toxicity has been exploited for cosmetic and therapeutic uses to treat a wide range of neuromuscular disorders. Although naturally occurring BoNT types share a common end effect, their activity varies significantly based on the neuronal cell-surface receptors and intracellular SNARE substrates they target. These properties are the result of structural variations that have traditionally been studied using biophysical methods such as X-ray crystallography. Here, we determined the first structures of botulinum neurotoxins using single-particle cryogenic electron microscopy. The maps obtained at 3.6 and 3.7 Å for BoNT/B and /E, respectively, highlight the subtle structural dynamism between domains, and of the binding domain in particular. This study demonstrates how the recent advances made in the field of single-particle electron microscopy can be applied to bacterial toxins of clinical relevance and the botulinum neurotoxin family in particular. Full article
(This article belongs to the Special Issue Structure and Function of Clostridial and Botulinum-Like Neurotoxins)
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15 pages, 2641 KiB  
Article
New Modified Recombinant Botulinum Neurotoxin Type F with Enhanced Potency
by David Burgin, Cindy Périer, Gavin Hackett, Mark Elliott, Daniel Kwan, Fraser Hornby, Imran Mir, Jacquie Maignel, Sai Man Liu and Matthew Beard
Toxins 2021, 13(12), 834; https://doi.org/10.3390/toxins13120834 - 24 Nov 2021
Cited by 3 | Viewed by 2857
Abstract
Botulinum neurotoxins (BoNTs) are notorious toxins and powerful agents and can be lethal, causing botulism, but they are also widely used as therapeutics, particularly to treat neuromuscular disorders. As of today, the commercial BoNT treatments available are from native A or B serotypes. [...] Read more.
Botulinum neurotoxins (BoNTs) are notorious toxins and powerful agents and can be lethal, causing botulism, but they are also widely used as therapeutics, particularly to treat neuromuscular disorders. As of today, the commercial BoNT treatments available are from native A or B serotypes. Serotype F has shown efficacy in a clinical trial but has scarcely been used, most likely due to its medium duration of effect. Previously, the uniqueness of the light chain of the F7 subtype was identified and reported, showing an extended interaction with its substrates, VAMPs 1, 2 and 3, and a superior catalytic activity compared to other BoNT/F subtypes. In order to more extensively study the properties of this neurotoxin, we engineered a modified F7 chimera, mrBoNT/F7-1, in which all the regions of the neurotoxin were identical to BoNT/F7 except the activation loop, which was the activation loop from BoNT/F1. Use of the activation loop from BoNT/F1 allowed easier post-translational proteolytic activation of the recombinant protein without otherwise affecting its properties. mrBoNT/F7-1 was expressed, purified and then tested in a suite of in vitro and in vivo assays. mrBoNT/F7-1 was active and showed enhanced potency in comparison to both native and recombinant BoNT/F1. Additionally, the safety profile remained comparable to BoNT/F1 despite the increased potency. This new modified recombinant toxin F7 could be further exploited to develop unique therapeutics to address unmet medical needs. Full article
(This article belongs to the Special Issue Structure and Function of Clostridial and Botulinum-Like Neurotoxins)
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Review

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22 pages, 782 KiB  
Review
BoNT/A in the Urinary Bladder—More to the Story than Silencing of Cholinergic Nerves
by Hodan Ibrahim, Jacquie Maignel, Fraser Hornby, Donna Daly and Matthew Beard
Toxins 2022, 14(1), 53; https://doi.org/10.3390/toxins14010053 - 12 Jan 2022
Cited by 5 | Viewed by 2701
Abstract
Botulinum neurotoxin (BoNT/A) is an FDA and NICE approved second-line treatment for overactive bladder (OAB) in patients either not responsive or intolerant to anti-cholinergic drugs. BoNT/A acts to weaken muscle contraction by blocking release of the neurotransmitter acetyl choline (ACh) at neuromuscular junctions. [...] Read more.
Botulinum neurotoxin (BoNT/A) is an FDA and NICE approved second-line treatment for overactive bladder (OAB) in patients either not responsive or intolerant to anti-cholinergic drugs. BoNT/A acts to weaken muscle contraction by blocking release of the neurotransmitter acetyl choline (ACh) at neuromuscular junctions. However, this biological activity does not easily explain all the observed effects in clinical and non-clinical studies. There are also conflicting reports of expression of the BoNT/A protein receptor, SV2, and intracellular target protein, SNAP-25, in the urothelium and bladder. This review presents the current evidence of BoNT/A’s effect on bladder sensation, potential mechanisms by which it might exert these effects and discusses recent advances in understanding the action of BoNT in bladder tissue. Full article
(This article belongs to the Special Issue Structure and Function of Clostridial and Botulinum-Like Neurotoxins)
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