Rossetto, O., Pirazzini, M. & Montecucco, C. Botulinum neurotoxins: genetic, structural and mechanistic insights. Nat. Rev. Microbiol. 12, 535–549 (2014).

Article  PubMed  CAS  Google Scholar 

Hill, K. K. et al. Recombination and insertion events involving the botulinum neurotoxin complex genes in Clostridium botulinum types A, B, E and F and Clostridium butyricum type E strains. BMC Biol. 7, 66 (2009).

Article  PubMed  PubMed Central  Google Scholar 

Hill, K. K. & Smith, T. J. Genetic diversity within Clostridium botulinum serotypes, botulinum neurotoxin gene clusters and toxin subtypes. Curr. Top. Microbiol. Immunol. 364, 1–20 (2013).

PubMed  Google Scholar 

Gu, S. & Jin, R. Assembly and function of the botulinum neurotoxin progenitor complex. Curr. Top. Microbiol. Immunol. 364, 21–44 (2013).

PubMed  CAS  Google Scholar 

East, A. K. & Collins, M. D. Conserved structure of genes encoding components of botulinum neurotoxin complex M and the sequence of the gene coding for the nontoxic component in nonproteolytic Clostridium botulinum type F. Curr. Microbiol. 29, 69–77 (1994).

Article  PubMed  CAS  Google Scholar 

Lam, K. H. & Jin, R. Architecture of the botulinum neurotoxin complex: a molecular machine for protection and delivery. Curr. Opin. Struct. Biol. 31, 89–95 (2015).

Article  PubMed  PubMed Central  CAS  Google Scholar 

Eswaramoorthy, S., Sun, J., Li, H., Singh, B. R. & Swaminathan, S. Molecular assembly of clostridium botulinum progenitor M complex of type E. Sci. Rep. 5, 17795–17795 (2015).

Article  PubMed  PubMed Central  CAS  Google Scholar 

East, A. K., Bhandari, M., Hielm, S. & Collins, M. D. Analysis of the botulinum neurotoxin type F gene clusters in proteolytic and nonproteolytic Clostridium botulinum and Clostridium barati. Curr. Microbiol. 37, 262–268 (1998).

Article  PubMed  CAS  Google Scholar 

Kubota, T. et al. Gene arrangement in the upstream region of Clostridium botulinum type E and Clostridium butyricum BL6340 progenitor toxin genes is different from that of other types. FEMS Microbiol. Lett. 158, 215–221 (1998).

Article  PubMed  CAS  Google Scholar 

Chen, Y., Korkeala, H., Aarnikunnas, J. & Lindstrom, M. Sequencing the botulinum neurotoxin gene and related genes in Clostridium botulinum type E strains reveals orfX3 and a novel type E neurotoxin subtype. J. Bacteriol. 189, 8643–8650 (2007).

Article  PubMed  PubMed Central  CAS  Google Scholar 

Contreras, E. et al. A neurotoxin that specifically targets Anopheles mosquitoes. Nat. Commun. 10, 2869 (2019).

Article  PubMed  PubMed Central  Google Scholar 

Gustafsson, R. et al. Crystal structures of OrfX2 and P47 from a botulinum neurotoxin OrfX-type gene cluster. FEBS Lett. 591, 3781–3792 (2017).

Article  PubMed  CAS  Google Scholar 

Gao, L. et al. Crystal structures of OrfX1, OrfX2 and the OrfX1–OrfX3 complex from the orfX gene cluster of botulinum neurotoxin E1. FEBS Lett. 597, 524–537 (2023).

Article  PubMed  PubMed Central  CAS  Google Scholar 

Kosenina, S. & Stenmark, P. Crystal structure of the OrfX1–OrfX3 complex from the PMP1 neurotoxin gene cluster. FEBS Lett. 597, 515–523 (2023).

Article  PubMed  CAS  Google Scholar 

Gu, S. et al. Botulinum neurotoxin is shielded by NTNHA in an interlocked complex. Science 335, 977–981 (2012).

Article  PubMed  PubMed Central  CAS  Google Scholar 

Lee, K. et al. Structure of a bimodular botulinum neurotoxin complex provides insights into its oral toxicity. PLoS Pathog. 9, e1003690 (2013).

Article  PubMed  PubMed Central  Google Scholar 

Lee, K. et al. Molecular basis for disruption of E-cadherin adhesion by botulinum neurotoxin A complex. Science 344, 1405–1410 (2014).

Article  PubMed  PubMed Central  CAS  Google Scholar 

Lam, K. H. et al. The hypothetical protein P47 of Clostridium botulinum E1 strain Beluga has a structural topology similar to bactericidal/permeability-increasing protein. Toxicon 147, 19–26 (2018).

Article  PubMed  CAS  Google Scholar 

Nowakowska, M. B., Douillard, F. P. & Lindström, M. Looking for the X factor in bacterial pathogenesis: association of orfX–p47 gene clusters with toxin genes in clostridial and non-clostridial bacterial species. Toxins (Basel) 12, 19 (2019).

Article  PubMed  Google Scholar 

Lin, G., Tepp, W. H., Pier, C. L., Jacobson, M. J. & Johnson, E. A. Expression of the Clostridium botulinum A2 neurotoxin gene cluster proteins and characterization of the A2 complex. Appl. Environ. Microbiol. 76, 40–47 (2010).

Article  PubMed  CAS  Google Scholar 

Lin, G., Tepp, W. H., Bradshaw, M., Fredrick, C. M. & Johnson, E. A. Immunoprecipitation of native botulinum neurotoxin complexes from Clostridium botulinum subtype A strains. Appl. Environ. Microbiol. 81, 481–491 (2015).

Article  PubMed  PubMed Central  Google Scholar 

Benefield, D. A., Dessain, S. K., Shine, N., Ohi, M. D. & Lacy, D. B. Molecular assembly of botulinum neurotoxin progenitor complexes. Proc. Natl Acad. Sci. USA 110, 5630–5635 (2013).

Article  PubMed  PubMed Central  CAS  Google Scholar 

Sakaguchi, Y. et al. Clostridium botulinum type A haemagglutinin-positive progenitor toxin (HA+-PTX) binds to oligosaccharides containing Galβ1–4GlcNAc through one subcomponent of haemagglutinin (HA1). Microbiology 147, 811–819 (2001).

Article  PubMed  Google Scholar 

Fujinaga, Y. et al. The haemagglutinin of Clostridium botulinum type C progenitor toxin plays an essential role in binding of toxin to the epithelial cells of guinea pig small intestine, leading to the efficient absorption of the toxin. Microbiology 143, 3841–3847 (1997).

Article  PubMed  CAS  Google Scholar 

Fujinaga, Y. et al. Molecular characterization of binding subcomponents of Clostridium botulinum type C progenitor toxin for intestinal epithelial cells and erythrocytes. Microbiology 150, 1529–1538 (2004).

Article  PubMed  CAS  Google Scholar 

Kojima, S. et al. Clostridium botulinum type A progenitor toxin binds to intestine-407 cells via N-acetyllactosamine moiety. Biochem. Biophys. Res. Commun. 331, 571–576 (2005).

Article  PubMed  CAS  Google Scholar 

Lee, K. et al. High-resolution crystal structure of HA33 of botulinum neurotoxin type B progenitor toxin complex. Biochem. Biophys. Res. Commun. 446, 568–573 (2014).

Article  PubMed  PubMed Central  CAS  Google Scholar 

Nakamura, T. et al. Binding properties of Clostridium botulinum type C progenitor toxin to mucins. Biochim. Biophys. Acta 1770, 551–555 (2007).

Article  PubMed  CAS  Google Scholar 

Matsumura, T. et al. The HA proteins of botulinum toxin disrupt intestinal epithelial intercellular junctions to increase toxin absorption. Cell. Microbiol. 10, 355–364 (2008).

PubMed  CAS  Google Scholar 

Sugawara, Y., Yutani, M., Amatsu, S., Matsumura, T. & Fujinaga, Y. Functional dissection of the Clostridium botulinum type B hemagglutinin complex: identification of the carbohydrate and E-cadherin binding sites. PLoS ONE 9, e111170 (2014).

Article  PubMed  PubMed Central  Google Scholar 

Sugawara, Y. et al. Botulinum hemagglutinin disrupts the intercellular epithelial barrier by directly binding E-cadherin. J. Cell Biol. 189, 691–700 (2010).

Article