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Annual Review of Biochemistry

Volume 88, 2019

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.

Keyword(s): bacterial toxin, botulinum neurotoxin, clostridium, protein engineering, tetanus neurotoxin, toxin
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/content/journals/10.1146/annurev-biochem-013118-111654
2019-06-20
2024-04-18
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Literature Cited

  1. 1. 
    Alouf JE. 2006. A 116-year story of bacterial protein toxins (1888–2004): from “diphtheritic poison” to molecular toxinology. The Comprehensive Sourcebook of Bacterial Protein Toxins J Alouf, M Popoff 3–21 Burlington, MA: Academic. , 3rd ed..
     [Google Scholar]
  2. 2. 
    Gill DM. 1982. Bacterial toxins: a table of lethal amounts. Microbiol. Rev. 46:86–94
     [Google Scholar]
  3. 3. 
    Schantz EJ, Johnson EA 1992. Properties and use of botulinum toxin and other microbial neurotoxins in medicine. Microbiol. Rev. 56:80–99
     [Google Scholar]
  4. 4. 
    Johnson EA. 1999. Clostridial toxins as therapeutic agents: benefits of nature's most toxic proteins. Annu. Rev. Microbiol. 53:551–75
     [Google Scholar]
  5. 5. 
    Arnon SS, Schechter R, Inglesby TV, Henderson DA, Bartlett JG et al. 2001. Botulinum toxin as a biological weapon: medical and public health management. JAMA 285:1059–70
     [Google Scholar]
  6. 6. 
    Schiavo G, Matteoli M, Montecucco C 2000. Neurotoxins affecting neuroexocytosis. Physiol. Rev. 80:717–66
     [Google Scholar]
  7. 7. 
    Rossetto O, Pirazzini M, Montecucco C 2014. Botulinum neurotoxins: genetic, structural and mechanistic insights. Nat. Rev. Microbiol. 12:535–49
     [Google Scholar]
  8. 8. 
    Lacy DB, Tepp W, Cohen AC, DasGupta BR, Stevens RC 1998. Crystal structure of botulinum neurotoxin type A and implications for toxicity. Nat. Struct. Biol. 5:898–902
     [Google Scholar]
  9. 9. 
    Swaminathan S, Eswaramoorthy S 2000. Structural analysis of the catalytic and binding sites of Clostridium botulinum neurotoxin B. Nat. Struct. Biol. 7:693–9
     [Google Scholar]
  10. 10. 
    Kumaran D, Eswaramoorthy S, Furey W, Navaza J, Sax M, Swaminathan S 2009. Domain organization in Clostridium botulinum neurotoxin type E is unique: its implication in faster translocation. J. Mol. Biol. 386:233–45
     [Google Scholar]
  11. 11. 
    Masuyer G, Conrad J, Stenmark P 2017. The structure of the tetanus toxin reveals pH-mediated domain dynamics. EMBO Rep 18:1306–17
     [Google Scholar]
  12. 12. 
    Jahn R, Scheller RH 2006. SNAREs—engines for membrane fusion. Nat. Rev. Mol. Cell Biol. 7:631–43
     [Google Scholar]
  13. 13. 
    Sudhof TC, Rothman JE 2009. Membrane fusion: grappling with SNARE and SM proteins. Science 323:474–77
     [Google Scholar]
  14. 14. 
    Zhou Q, Zhou P, Wang AL, Wu D, Zhao M et al. 2017. The primed SNARE-complexin-synaptotagmin complex for neuronal exocytosis. Nature 548:420–25
     [Google Scholar]
  15. 15. 
    Schiavo G, Benfenati F, Poulain B, Rossetto O, Polverino de Laureto P et al. 1992. Tetanus and botulinum-B neurotoxins block neurotransmitter release by proteolytic cleavage of synaptobrevin. Nature 359:832–35
     [Google Scholar]
  16. 16. 
    Sollner T, Whiteheart SW, Brunner M, Erdjument-Bromage H, Geromanos S et al. 1993. SNAP receptors implicated in vesicle targeting and fusion. Nature 362:318–24
     [Google Scholar]
  17. 17. 
    Montal M. 2010. Botulinum neurotoxin: a marvel of protein design. Annu. Rev. Biochem. 79:591–617
     [Google Scholar]
  18. 18. 
    Rummel A. 2015. The long journey of botulinum neurotoxins into the synapse. Toxicon 107:9–24
     [Google Scholar]
  19. 19. 
    Pirazzini M, Rossetto O, Eleopra R, Montecucco C 2017. Botulinum neurotoxins: biology, pharmacology, and toxicology. Pharmacol. Rev. 69:200–35
     [Google Scholar]
  20. 20. 
    Gu S, Rumpel S, Zhou J, Strotmeier J, Bigalke H et al. 2012. Botulinum neurotoxin is shielded by NTNHA in an interlocked complex. Science 335:977–81
     [Google Scholar]
  21. 21. 
    Eswaramoorthy S, Sun J, Li H, Singh BR, Swaminathan S 2015. Molecular assembly of Clostridium botulinum progenitor M complex of type E. Sci. Rep. 5:17795
     [Google Scholar]
  22. 22. 
    Benefield DA, Dessain SK, Shine N, Ohi MD, Lacy DB 2013. Molecular assembly of botulinum neurotoxin progenitor complexes. PNAS 110:5630–35
     [Google Scholar]
  23. 23. 
    Lee K, Gu S, Jin L, Le TT, Cheng LW et al. 2013. Structure of a bimodular botulinum neurotoxin complex provides insights into its oral toxicity. PLOS Pathog 9:e1003690
     [Google Scholar]
  24. 24. 
    Hasegawa K, Watanabe T, Suzuki T, Yamano A, Oikawa T et al. 2007. A novel subunit structure of Clostridium botulinum serotype D toxin complex with three extended arms. J. Biol. Chem. 282:24777–83
     [Google Scholar]
  25. 25. 
    Amatsu S, Sugawara Y, Matsumura T, Kitadokoro K, Fujinaga Y 2013. Crystal structure of Clostridium botulinum whole hemagglutinin reveals a huge triskelion-shaped molecular complex. J. Biol. Chem. 288:35617–25
     [Google Scholar]
  26. 26. 
    Matsumura T, Sugawara Y, Yutani M, Amatsu S, Yagita H et al. 2015. Botulinum toxin A complex exploits intestinal M cells to enter the host and exert neurotoxicity. Nat. Commun. 6:6255
     [Google Scholar]
  27. 27. 
    Sugawara Y, Matsumura T, Takegahara Y, Jin Y, Tsukasaki Y et al. 2010. Botulinum hemagglutinin disrupts the intercellular epithelial barrier by directly binding E-cadherin. J. Cell Biol. 189:691–700
     [Google Scholar]
  28. 28. 
    Lee K, Zhong X, Gu S, Kruel AM, Dorner MB et al. 2014. Molecular basis for disruption of E-cadherin adhesion by botulinum neurotoxin A complex. Science 344:1405–10
     [Google Scholar]
  29. 29. 
    Miyashita S, Sagane Y, Suzuki T, Matsumoto T, Niwa K, Watanabe T 2016. “Non-toxic” proteins of the botulinum toxin complex exert in-vivo toxicity. Sci. Rep. 6:31043
     [Google Scholar]
  30. 30. 
    Kalb SR, Baudys J, Smith TJ, Smith LA, Barr JR 2017. Characterization of hemagglutinin negative botulinum progenitor toxins. Toxins 9:193
     [Google Scholar]
  31. 31. 
    Gustafsson R, Berntsson RP, Martinez-Carranza M, El Tekle G, Odegrip R et al. 2017. Crystal structures of OrfX2 and P47 from a botulinum neurotoxin OrfX-type gene cluster. FEBS Lett 591:3781–92
     [Google Scholar]
  32. 32. 
    Lam KH, Qi R, Liu S, Kroh A, Yao G et al. 2018. The hypothetical protein P47 of Clostridium botulinum E1 strain Beluga has a structural topology similar to bactericidal/permeability-increasing protein. Toxicon 147:19–26
     [Google Scholar]
  33. 33. 
    Montecucco C. 1986. How do tetanus and botulinum toxins bind to neuronal membranes?. Trends Biochem. Sci. 11:314–17
     [Google Scholar]
  34. 34. 
    Van Heyningen WE, Miller PA 1961. The fixation of tetanus toxin by ganglioside. J. Gen. Microbiol. 24:107–19
     [Google Scholar]
  35. 35. 
    Simpson LL, Rapport MM 1971. Ganglioside inactivation of botulinum toxin. J. Neurochem. 18:1341–43
     [Google Scholar]
  36. 36. 
    Kitamura M, Takamiya K, Aizawa S, Furukawa K 1999. Gangliosides are the binding substances in neural cells for tetanus and botulinum toxins in mice. Biochim. Biophys. Acta 1441:1–3
     [Google Scholar]
  37. 37. 
    Tsukamoto K, Kohda T, Mukamoto M, Takeuchi K, Ihara H et al. 2005. Binding of Clostridium botulinum type C and D neurotoxins to ganglioside and phospholipid: novel insights into the receptor for clostridial neurotoxins. J. Biol. Chem. 280:35164–71
     [Google Scholar]
  38. 38. 
    Dong M, Tepp WH, Liu H, Johnson EA, Chapman ER 2007. Mechanism of botulinum neurotoxin B and G entry into hippocampal neurons. J. Cell Biol. 179:1511–22
     [Google Scholar]
  39. 39. 
    Bullens RW, O'Hanlon GM, Wagner E, Molenaar PC, Furukawa K et al. 2002. Complex gangliosides at the neuromuscular junction are membrane receptors for autoantibodies and botulinum neurotoxin but redundant for normal synaptic function. J. Neurosci. 22:6876–84
     [Google Scholar]
  40. 40. 
    Dong M, Liu H, Tepp WH, Johnson EA, Janz R, Chapman ER 2008. Glycosylated SV2A and SV2B mediate the entry of botulinum neurotoxin E into neurons. Mol. Biol. Cell 19:5226–37
     [Google Scholar]
  41. 41. 
    Rummel A, Hafner K, Mahrhold S, Darashchonak N, Holt M et al. 2009. Botulinum neurotoxins C, E and F bind gangliosides via a conserved binding site prior to stimulation-dependent uptake with botulinum neurotoxin F utilising the three isoforms of SV2 as second receptor. J. Neurochem. 110:1942–54
     [Google Scholar]
  42. 42. 
    Strotmeier J, Lee K, Volker AK, Mahrhold S, Zong Y et al. 2010. Botulinum neurotoxin serotype D attacks neurons via two carbohydrate-binding sites in a ganglioside-dependent manner. Biochem. J. 431:207–16
     [Google Scholar]
  43. 43. 
    Strotmeier J, Gu S, Jutzi S, Mahrhold S, Zhou J et al. 2011. The biological activity of botulinum neurotoxin type C is dependent upon novel types of ganglioside binding sites. Mol. Microbiol. 81:143–56
     [Google Scholar]
  44. 44. 
    Peng L, Tepp WH, Johnson EA, Dong M 2011. Botulinum neurotoxin D uses synaptic vesicle protein SV2 and gangliosides as receptors. PLOS Pathog 7:e1002008
     [Google Scholar]
  45. 45. 
    Zhang S, Berntsson RPA, Tepp WH, Tao L, Johnson EA et al. 2017. Structural basis for the unique ganglioside and cell membrane recognition mechanism of botulinum neurotoxin DC. Nat. Commun. 8:1637
     [Google Scholar]
  46. 46. 
    Fotinou C, Emsley P, Black I, Ando H, Ishida H et al. 2001. The crystal structure of tetanus toxin Hc fragment complexed with a synthetic GT1b analogue suggests cross-linking between ganglioside receptors and the toxin. J. Biol. Chem. 276:32274–81
     [Google Scholar]
  47. 47. 
    Rummel A, Bade S, Alves J, Bigalke H, Binz T 2003. Two carbohydrate binding sites in the H(CC)-domain of tetanus neurotoxin are required for toxicity. J. Mol. Biol. 326:835–47
     [Google Scholar]
  48. 48. 
    Rummel A, Mahrhold S, Bigalke H, Binz T 2004. The HCC-domain of botulinum neurotoxins A and B exhibits a singular ganglioside binding site displaying serotype specific carbohydrate interaction. Mol. Microbiol. 51:631–43
     [Google Scholar]
  49. 49. 
    Stenmark P, Dupuy J, Imamura A, Kiso M, Stevens RC 2008. Crystal structure of botulinum neurotoxin type A in complex with the cell surface co-receptor GT1b-insight into the toxin-neuron interaction. PLOS Pathog 4:e1000129
     [Google Scholar]
  50. 50. 
    Berntsson RP, Peng L, Dong M, Stenmark P 2013. Structure of dual receptor binding to botulinum neurotoxin B. Nat. Commun. 4:2058
     [Google Scholar]
  51. 51. 
    Benson MA, Fu Z, Kim JJ, Baldwin MR 2011. Unique ganglioside recognition strategies for clostridial neurotoxins. J. Biol. Chem. 286:34015–22
     [Google Scholar]
  52. 52. 
    Hamark C, Berntsson RP, Masuyer G, Henriksson LM, Gustafsson R et al. 2017. Glycans confer specificity to the recognition of ganglioside receptors by botulinum neurotoxin A. J. Am. Chem. Soc. 139:218–30
     [Google Scholar]
  53. 53. 
    Jayaraman S, Eswaramoorthy S, Kumaran D, Swaminathan S 2005. Common binding site for disialyllactose and tri-peptide in C-fragment of tetanus neurotoxin. Proteins 61:288–95
     [Google Scholar]
  54. 54. 
    Chen C, Fu Z, Kim JJ, Barbieri JT, Baldwin MR 2009. Gangliosides as high affinity receptors for tetanus neurotoxin. J. Biol. Chem. 284:26569–77
     [Google Scholar]
  55. 55. 
    Moriishi K, Koura M, Abe N, Fujii N, Fujinaga Y et al. 1996. Mosaic structures of neurotoxins produced from Clostridium botulinum types C and D organisms. Biochim. Biophys. Acta 1307:123–26
     [Google Scholar]
  56. 56. 
    Nishiki T, Kamata Y, Nemoto Y, Omori A, Ito T et al. 1994. Identification of protein receptor for Clostridium botulinum type B neurotoxin in rat brain synaptosomes. J. Biol. Chem. 269:10498–503
     [Google Scholar]
  57. 57. 
    Nishiki T, Tokuyama Y, Kamata Y, Nemoto Y, Yoshida A et al. 1996. The high-affinity binding of Clostridium botulinum type B neurotoxin to synaptotagmin II associated with gangliosides GT1b/GD1a. FEBS Lett 378:253–57
     [Google Scholar]
  58. 58. 
    Dong M, Richards DA, Goodnough MC, Tepp WH, Johnson EA, Chapman ER 2003. Synaptotagmins I and II mediate entry of botulinum neurotoxin B into cells. J. Cell Biol. 162:1293–303
     [Google Scholar]
  59. 59. 
    Rummel A, Karnath T, Henke T, Bigalke H, Binz T 2004. Synaptotagmins I and II act as nerve cell receptors for botulinum neurotoxin G. J. Biol. Chem. 279:30865–70
     [Google Scholar]
  60. 60. 
    Peng L, Berntsson RP, Tepp WH, Pitkin RM, Johnson EA et al. 2012. Botulinum neurotoxin D-C uses synaptotagmin I and II as receptors, and human synaptotagmin II is not an effective receptor for type B, D-C and G toxins. J. Cell Sci. 125:3233–42
     [Google Scholar]
  61. 61. 
    Chapman ER. 2002. Synaptotagmin: a Ca2+ sensor that triggers exocytosis?. Nat. Rev. Mol. Cell Biol. 3:498–508
     [Google Scholar]
  62. 62. 
    Chai Q, Arndt JW, Dong M, Tepp WH, Johnson EA et al. 2006. Structural basis of cell surface receptor recognition by botulinum neurotoxin B. Nature 444:1096–100
     [Google Scholar]
  63. 63. 
    Rummel A, Eichner T, Weil T, Karnath T, Gutcaits A et al. 2007. Identification of the protein receptor binding site of botulinum neurotoxins B and G proves the double-receptor concept. PNAS 104:359–64
     [Google Scholar]
  64. 64. 
    Pang ZP, Melicoff E, Padgett D, Liu Y, Teich AF et al. 2006. Synaptotagmin-2 is essential for survival and contributes to Ca2+ triggering of neurotransmitter release in central and neuromuscular synapses. J. Neurosci. 26:13493–504
     [Google Scholar]
  65. 65. 
    Jin R, Rummel A, Binz T, Brunger AT 2006. Botulinum neurotoxin B recognizes its protein receptor with high affinity and specificity. Nature 444:1092–95
     [Google Scholar]
  66. 66. 
    Strotmeier J, Willjes G, Binz T, Rummel A 2012. Human synaptotagmin-II is not a high affinity receptor for botulinum neurotoxin B and G: increased therapeutic dosage and immunogenicity. FEBS Lett 586:310–13
     [Google Scholar]
  67. 67. 
    Stenmark P, Dong M, Dupuy J, Chapman ER, Stevens RC 2010. Crystal structure of the botulinum neurotoxin type G binding domain: insight into cell surface binding. J. Mol. Biol. 397:1287–97
     [Google Scholar]
  68. 68. 
    Willjes G, Mahrhold S, Strotmeier J, Eichner T, Rummel A, Binz T 2013. Botulinum neurotoxin G binds synaptotagmin-II in a mode similar to that of serotype B: tyrosine 1186 and lysine 1191 cause its lower affinity. Biochemistry 52:3930–38
     [Google Scholar]
  69. 69. 
    Berntsson RP, Peng L, Svensson LM, Dong M, Stenmark P 2013. Crystal structures of botulinum neurotoxin DC in complex with its protein receptors synaptotagmin I and II. Structure 21:1602–11
     [Google Scholar]
  70. 70. 
    Dong M, Yeh F, Tepp WH, Dean C, Johnson EA et al. 2006. SV2 is the protein receptor for botulinum neurotoxin A. Science 312:592–96
     [Google Scholar]
  71. 71. 
    Mahrhold S, Rummel A, Bigalke H, Davletov B, Binz T 2006. The synaptic vesicle protein 2C mediates the uptake of botulinum neurotoxin A into phrenic nerves. FEBS Lett 580:2011–14
     [Google Scholar]
  72. 72. 
    Colasante C, Rossetto O, Morbiato L, Pirazzini M, Molgo J, Montecucco C 2013. Botulinum neurotoxin type A is internalized and translocated from small synaptic vesicles at the neuromuscular junction. Mol. Neurobiol. 48:120–27
     [Google Scholar]
  73. 73. 
    Chakkalakal JV, Nishimune H, Ruas JL, Spiegelman BM, Sanes JR 2010. Retrograde influence of muscle fibers on their innervation revealed by a novel marker for slow motoneurons. Development 137:3489–99
     [Google Scholar]
  74. 74. 
    Benoit RM, Frey D, Hilbert M, Kevenaar JT, Wieser MM et al. 2014. Structural basis for recognition of synaptic vesicle protein 2C by botulinum neurotoxin A. Nature 505:108–11
     [Google Scholar]
  75. 75. 
    Yao G, Zhang S, Mahrhold S, Lam KH, Stern D et al. 2016. N-linked glycosylation of SV2 is required for binding and uptake of botulinum neurotoxin A. Nat. Struct. Mol. Biol. 23:656–62
     [Google Scholar]
  76. 76. 
    Mahrhold S, Bergstrom T, Stern D, Dorner BG, Astot C, Rummel A 2016. Only the complex N559-glycan in the synaptic vesicle glycoprotein 2C mediates high affinity binding to botulinum neurotoxin serotype A1. Biochem. J. 473:2645–54
     [Google Scholar]
  77. 77. 
    Garcia-Rodriguez C, Levy R, Arndt JW, Forsyth CM, Razai A et al. 2007. Molecular evolution of antibody cross-reactivity for two subtypes of type A botulinum neurotoxin. Nat. Biotechnol. 25:107–16
     [Google Scholar]
  78. 78. 
    Mahrhold S, Strotmeier J, Garcia-Rodriguez C, Lou J, Marks JD et al. 2013. Identification of the SV2 protein receptor-binding site of botulinum neurotoxin type E. Biochem. J. 453:37–47
     [Google Scholar]
  79. 79. 
    Yeh FL, Dong M, Yao J, Tepp WH, Lin G et al. 2010. SV2 mediates entry of tetanus neurotoxin into central neurons. PLOS Pathog 6:e1001207
     [Google Scholar]
  80. 80. 
    Bercsenyi K, Schmieg N, Bryson JB, Wallace M, Caccin P et al. 2014. Tetanus toxin entry. Nidogens are therapeutic targets for the prevention of tetanus. Science 346:1118–23
     [Google Scholar]
  81. 81. 
    Fu Z, Chen C, Barbieri JT, Kim JJ, Baldwin MR 2009. Glycosylated SV2 and gangliosides as dual receptors for botulinum neurotoxin serotype F. Biochemistry 48:5631–41
     [Google Scholar]
  82. 82. 
    Jacky BP, Garay PE, Dupuy J, Nelson JB, Cai B et al. 2013. Identification of fibroblast growth factor receptor 3 (FGFR3) as a protein receptor for botulinum neurotoxin serotype A (BoNT/A). PLOS Pathog 9:e1003369
     [Google Scholar]
  83. 83. 
    Strotmeier J, Lee K, Volker AK, Mahrhold S, Zong Y et al. 2010. Botulinum neurotoxin serotype D attacks neurons via two carbohydrate binding sites in a ganglioside-dependent manner. Biochem. J. 431:207–16
     [Google Scholar]
  84. 84. 
    Karalewitz AP, Fu Z, Baldwin MR, Kim JJ, Barbieri JT 2012. Botulinum neurotoxin serotype C associates with dual ganglioside receptors to facilitate cell entry. J. Biol. Chem. 287:40806–16
     [Google Scholar]
  85. 85. 
    Kroken AR, Karalewitz AP, Fu Z, Kim JJ, Barbieri JT 2011. Novel ganglioside-mediated entry of botulinum neurotoxin serotype D into neurons. J. Biol. Chem. 286:26828–37
     [Google Scholar]
  86. 86. 
    Kroken AR, Karalewitz AP, Fu Z, Baldwin MR, Kim JJ, Barbieri JT 2011. Unique ganglioside binding by botulinum neurotoxins C and D-SA. FEBS J 278:4486–96
     [Google Scholar]
  87. 87. 
    Stern D, Weisemann J, Le Blanc A, von Berg L, Mahrhold S et al. 2018. A lipid-binding loop of botulinum neurotoxin serotypes B, DC and G is an essential feature to confer their exquisite potency. PLOS Pathog 14:e1007048
     [Google Scholar]
  88. 88. 
    Surana S, Tosolini AP, Meyer IFG, Fellows AD, Novoselov SS, Schiavo G 2018. The travel diaries of tetanus and botulinum neurotoxins. Toxicon 147:58–67
     [Google Scholar]
  89. 89. 
    Bercsenyi K, Giribaldi F, Schiavo G 2013. The elusive compass of clostridial neurotoxins: deciding when and where to go?. Curr. Top. Microbiol. Immunol. 364:91–113
     [Google Scholar]
  90. 90. 
    Wang J, Zurawski TH, Meng J, Lawrence GW, Aoki KR et al. 2012. Novel chimeras of botulinum and tetanus neurotoxins yield insights into their distinct sites of neuroparalysis. FASEB J 26:5035–48
     [Google Scholar]
  91. 91. 
    Ovsepian SV, Bodeker M, O'Leary VB, Lawrence GW, Dolly JO 2015. Internalization and retrograde axonal trafficking of tetanus toxin in motor neurons and trans-synaptic propagation at central synapses exceed those of its C-terminal-binding fragments. Brain Struct. Funct. 220:1825–38
     [Google Scholar]
  92. 92. 
    Blum FC, Przedpelski A, Tepp WH, Johnson EA, Barbieri JT 2014. Entry of a recombinant, full-length, atoxic tetanus neurotoxin into Neuro-2a cells. Infect. Immun. 82:873–81
     [Google Scholar]
  93. 93. 
    Blum FC, Tepp WH, Johnson EA, Barbieri JT 2014. Multiple domains of tetanus toxin direct entry into primary neurons. Traffic 15:1057–65
     [Google Scholar]
  94. 94. 
    Matsuda M, Sugimoto N, Ozutsumi K, Hirai T 1982. Acute botulinum-like intoxication by tetanus neurotoxin in mice. Biochem. Biophys. Res. Commun. 104:799–805
     [Google Scholar]
  95. 95. 
    Wiegand H, Erdmann G, Wellhoner HH 1976. 125I-labelled botulinum A neurotoxin: pharmacokinetics in cats after intramuscular injection. Naunyn-Schmiedeberg's Arch. Pharmacol. 292:161–65
     [Google Scholar]
  96. 96. 
    Antonucci F, Rossi C, Gianfranceschi L, Rossetto O, Caleo M 2008. Long-distance retrograde effects of botulinum neurotoxin A. J. Neurosci. 28:3689–96
     [Google Scholar]
  97. 97. 
    Restani L, Novelli E, Bottari D, Leone P, Barone I et al. 2012. Botulinum neurotoxin A impairs neurotransmission following retrograde transynaptic transport. Traffic 13:1083–89
     [Google Scholar]
  98. 98. 
    Restani L, Giribaldi F, Manich M, Bercsenyi K, Menendez G et al. 2012. Botulinum neurotoxins A and E undergo retrograde axonal transport in primary motor neurons. PLOS Pathog 8:e1003087
     [Google Scholar]
  99. 99. 
    Bomba-Warczak E, Vevea JD, Brittain JM, Figueroa-Bernier A, Tepp WH et al. 2016. Interneuronal transfer and distal action of tetanus toxin and botulinum neurotoxins A and D in central neurons. Cell Rep 16:1974–87
     [Google Scholar]
  100. 100. 
    Pirazzini M, Tehran DA, Zanetti G, Lista F, Binz T et al. 2015. The thioredoxin reductase–Thioredoxin redox system cleaves the interchain disulphide bond of botulinum neurotoxins on the cytosolic surface of synaptic vesicles. Toxicon 107:32–36
     [Google Scholar]
  101. 101. 
    Pirazzini M, Azarnia Tehran D, Zanetti G, Megighian A, Scorzeto M et al. 2014. Thioredoxin and its reductase are present on synaptic vesicles, and their inhibition prevents the paralysis induced by botulinum neurotoxins. Cell Rep 8:1870–78
     [Google Scholar]
  102. 102. 
    Pirazzini M, Tehran DA, Leka O, Zanetti G, Rossetto O, Montecucco C 2016. On the translocation of botulinum and tetanus neurotoxins across the membrane of acidic intracellular compartments. Biochim. Biophys. Acta 1858:467–74
     [Google Scholar]
  103. 103. 
    Fischer A, Montal M 2007. Single molecule detection of intermediates during botulinum neurotoxin translocation across membranes. PNAS 104:10447–52
     [Google Scholar]
  104. 104. 
    Koriazova LK, Montal M 2003. Translocation of botulinum neurotoxin light chain protease through the heavy chain channel. Nat. Struct. Biol. 10:13–18
     [Google Scholar]
  105. 105. 
    Fischer A, Montal M 2007. Crucial role of the disulfide bridge between botulinum neurotoxin light and heavy chains in protease translocation across membranes. J. Biol. Chem. 282:29604–11
     [Google Scholar]
  106. 106. 
    Montecucco C, Schiavo G, Brunner J, Duflot E, Boquet P, Roa M 1986. Tetanus toxin is labeled with photoactivatable phospholipids at low pH. Biochemistry 25:919–24
     [Google Scholar]
  107. 107. 
    Montecucco C, Schiavo G, Dasgupta BR 1989. Effect of pH on the interaction of botulinum neurotoxins A, B and E with liposomes. Biochem. J. 259:47–53
     [Google Scholar]
  108. 108. 
    Berliocchi L, Fava E, Leist M, Horvat V, Dinsdale D et al. 2005. Botulinum neurotoxin C initiates two different programs for neurite degeneration and neuronal apoptosis. J. Cell Biol. 168:607–18
     [Google Scholar]
  109. 109. 
    Peng L, Liu H, Ruan H, Tepp WH, Stoothoff WH et al. 2013. Cytotoxicity of botulinum neurotoxins reveals a direct role of syntaxin 1 and SNAP-25 in neuron survival. Nat. Commun. 4:1472
     [Google Scholar]
  110. 110. 
    Rawlings ND, Barrett AJ, Bateman A 2010. MEROPS: the peptidase database. Nucleic Acids Res 38:D227–33
     [Google Scholar]
  111. 111. 
    Binz T, Bade S, Rummel A, Kollewe A, Alves J 2002. Arg362 and Tyr365 of the botulinum neurotoxin type a light chain are involved in transition state stabilization. Biochemistry 41:1717–23
     [Google Scholar]
  112. 112. 
    Rossetto O, Schiavo G, Montecucco C, Poulain B, Deloye F et al. 1994. SNARE motif and neurotoxins. Nature 372:415–16
     [Google Scholar]
  113. 113. 
    Breidenbach MA, Brunger AT 2004. Substrate recognition strategy for botulinum neurotoxin serotype A. Nature 432:925–29
     [Google Scholar]
  114. 114. 
    Agarwal R, Schmidt JJ, Stafford RG, Swaminathan S 2009. Mode of VAMP substrate recognition and inhibition of Clostridium botulinum neurotoxin F. Nat. Struct. Mol. Biol. 16:789–94
     [Google Scholar]
  115. 115. 
    Yamasaki S, Baumeister A, Binz T, Blasi J, Link E et al. 1994. Cleavage of members of the synaptobrevin/VAMP family by types D and F botulinal neurotoxins and tetanus toxin. J. Biol. Chem. 269:12764–72
     [Google Scholar]
  116. 116. 
    Peng L, Adler M, Demogines A, Borrell A, Liu H et al. 2014. Widespread sequence variations in VAMP1 across vertebrates suggest a potential selective pressure from botulinum neurotoxins. PLOS Pathog 10:e1004177
     [Google Scholar]
  117. 117. 
    Whitemarsh RC, Tepp WH, Johnson EA, Pellett S 2014. Persistence of botulinum neurotoxin A subtypes 1–5 in primary rat spinal cord cells. PLOS ONE 9:e90252
     [Google Scholar]
  118. 118. 
    Keller JE, Neale EA, Oyler G, Adler M 1999. Persistence of botulinum neurotoxin action in cultured spinal cord cells. FEBS Lett 456:137–42
     [Google Scholar]
  119. 119. 
    Vagin O, Tokhtaeva E, Garay PE, Souda P, Bassilian S et al. 2014. Recruitment of septin cytoskeletal proteins by botulinum toxin A protease determines its remarkable stability. J. Cell Sci. 127:3294–308
     [Google Scholar]
  120. 120. 
    Wang J, Zurawski TH, Meng J, Lawrence G, Olango WM et al. 2011. A dileucine in the protease of botulinum toxin A underlies its long-lived neuroparalysis: transfer of longevity to a novel potential therapeutic. J. Biol. Chem. 286:6375–85
     [Google Scholar]
  121. 121. 
    Scheps D, Lopez de la Paz M, Jurk M, Hofmann F, Frevert J 2017. Design of modified botulinum neurotoxin A1 variants with a shorter persistence of paralysis and duration of action. Toxicon 139:101–8
     [Google Scholar]
  122. 122. 
    Tsai YC, Kotiya A, Kiris E, Yang M, Bavari S et al. 2017. Deubiquitinating enzyme VCIP135 dictates the duration of botulinum neurotoxin type A intoxication. PNAS 114:E5158–66
     [Google Scholar]
  123. 123. 
    Tsai YC, Maditz R, Kuo CL, Fishman PS, Shoemaker CB et al. 2010. Targeting botulinum neurotoxin persistence by the ubiquitin-proteasome system. PNAS 107:16554–59
     [Google Scholar]
  124. 124. 
    Wang J, Meng J, Lawrence GW, Zurawski TH, Sasse A et al. 2008. Novel chimeras of botulinum neurotoxins A and E unveil contributions from the binding, translocation, and protease domains to their functional characteristics. J. Biol. Chem. 283:16993–7002
     [Google Scholar]
  125. 125. 
    Foran PG, Mohammed N, Lisk GO, Nagwaney S, Lawrence GW et al. 2003. Evaluation of the therapeutic usefulness of botulinum neurotoxin B, C1, E, and F compared with the long lasting type A. Basis for distinct durations of inhibition of exocytosis in central neurons. J. Biol. Chem. 278:1363–71
     [Google Scholar]
  126. 126. 
    Hill KK, Smith TJ, Helma CH, Ticknor LO, Foley BT et al. 2007. Genetic diversity among botulinum neurotoxin-producing clostridial strains. J. Bacteriol. 189:818–32
     [Google Scholar]
  127. 127. 
    Hill KK, Xie G, Foley BT, Smith TJ 2015. Genetic diversity within the botulinum neurotoxin-producing bacteria and their neurotoxins. Toxicon 107:2–8
     [Google Scholar]
  128. 128. 
    Kalb SR, Baudys J, Webb RP, Wright P, Smith TJ et al. 2012. Discovery of a novel enzymatic cleavage site for botulinum neurotoxin F5. FEBS Lett 586:109–15
     [Google Scholar]
  129. 129. 
    Barash JR, Arnon SS 2014. A novel strain of Clostridium botulinum that produces type B and type H botulinum toxins. J. Infect. Dis. 209:183–91
     [Google Scholar]
  130. 130. 
    Dover N, Barash JR, Hill KK, Xie G, Arnon SS 2014. Molecular characterization of a novel botulinum neurotoxin type H gene. J. Infect. Dis. 209:192–202
     [Google Scholar]
  131. 131. 
    Maslanka SE, Luquez C, Dykes JK, Tepp WH, Pier CL et al. 2016. A novel botulinum neurotoxin, previously reported as serotype H, has a hybrid-like structure with regions of similarity to the structures of serotypes A and F and is neutralized with serotype A antitoxin. J. Infect. Dis. 213:379–85
     [Google Scholar]
  132. 132. 
    Kozaki S, Kamata Y, Nishiki T, Kakinuma H, Maruyama H et al. 1998. Characterization of Clostridium botulinum type B neurotoxin associated with infant botulism in Japan. Infect. Immun. 66:4811–16
     [Google Scholar]
  133. 133. 
    Zhang S, Masuyer G, Zhang J, Shen Y, Lundin D et al. 2017. Identification and characterization of a novel botulinum neurotoxin. Nat. Commun. 8:14130
     [Google Scholar]
  134. 134. 
    Zhang S, Lebreton F, Mansfield MJ, Miyashita SI, Zhang J et al. 2018. Identification of a botulinum neurotoxin-like toxin in a commensal strain of Enterococcus faecium. . Cell Host Microbe 23:169–76.e6
     [Google Scholar]
  135. 135. 
    Brunt J, Carter AT, Stringer SC, Peck MW 2018. Identification of a novel botulinum neurotoxin gene cluster in Enterococcus. . FEBS Lett 592:310–17
     [Google Scholar]
  136. 136. 
    Mansfield MJ, Adams JB, Doxey AC 2015. Botulinum neurotoxin homologs in non-Clostridium species. FEBS Lett 589:342–48
     [Google Scholar]
  137. 137. 
    Zornetta I, Azarnia Tehran D, Arrigoni G, Anniballi F, Bano L et al. 2016. The first non Clostridial botulinum-like toxin cleaves VAMP within the juxtamembrane domain. Sci. Rep. 6:30257
     [Google Scholar]
  138. 138. 
    Doxey AC, Mansfield MJ, Montecucco C 2018. Discovery of novel bacterial toxins by genomics and computational biology. Toxicon 147:2–12
     [Google Scholar]
  139. 139. 
    Montecucco C, Rasotto MB 2015. On botulinum neurotoxin variability. mBio 6:e02131–14
     [Google Scholar]
  140. 140. 
    Tao L, Peng L, Berntsson RP, Liu SM, Park S et al. 2017. Engineered botulinum neurotoxin B with improved efficacy for targeting human receptors. Nat. Commun. 8:53
     [Google Scholar]
  141. 141. 
    Burns JR, Lambert GS, Baldwin MR 2017. Insights into the mechanisms by which clostridial neurotoxins discriminate between gangliosides. Biochemistry 56:2571–83
     [Google Scholar]
  142. 142. 
    Guo J, Pan X, Zhao Y, Chen S 2013. Engineering clostridia neurotoxins with elevated catalytic activity. Toxicon 74:158–66
     [Google Scholar]
  143. 143. 
    Elliott M, Maignel J, Liu SM, Favre-Guilmard C, Mir I et al. 2017. Augmentation of VAMP-catalytic activity of botulinum neurotoxin serotype B does not result in increased potency in physiological systems. PLOS ONE 12:e0185628
     [Google Scholar]
  144. 144. 
    Lopez de la Paz M, Scheps D, Jurk M, Hofmann F, Frevert J 2018. Rational design of botulinum neurotoxin A1 mutants with improved oxidative stability. Toxicon 147:54–57
     [Google Scholar]
  145. 145. 
    Wang D, Zhang Z, Dong M, Sun S, Chapman ER, Jackson MB 2011. Syntaxin requirement for Ca2+-triggered exocytosis in neurons and endocrine cells demonstrated with an engineered neurotoxin. Biochemistry 50:2711–13
     [Google Scholar]
  146. 146. 
    Zanetti G, Sikorra S, Rummel A, Krez N, Duregotti E et al. 2017. Botulinum neurotoxin C mutants reveal different effects of syntaxin or SNAP-25 proteolysis on neuromuscular transmission. PLOS Pathog 13:e1006567
     [Google Scholar]
  147. 147. 
    Pirazzini M, Henke T, Rossetto O, Mahrhold S, Krez N et al. 2013. Neutralisation of specific surface carboxylates speeds up translocation of botulinum neurotoxin type B enzymatic domain. FEBS Lett 587:3831–36
     [Google Scholar]
  148. 148. 
    Rummel A, Mahrhold S, Bigalke H, Binz T 2011. Exchange of the HCC domain mediating double receptor recognition improves the pharmacodynamic properties of botulinum neurotoxin. FEBS J 278:4506–15
     [Google Scholar]
  149. 149. 
    Takamori S, Holt M, Stenius K, Lemke EA, Gronborg M et al. 2006. Molecular anatomy of a trafficking organelle. Cell 127:831–46
     [Google Scholar]
  150. 150. 
    Sikorra S, Litschko C, Muller C, Thiel N, Galli T et al. 2016. Identification and characterization of botulinum neurotoxin A substrate binding pockets and their re-engineering for human SNAP-23. J. Mol. Biol. 428:372–84
     [Google Scholar]
  151. 151. 
    Chen S, Barbieri JT 2009. Engineering botulinum neurotoxin to extend therapeutic intervention. PNAS 106:9180–84
     [Google Scholar]
  152. 152. 
    Somm E, Bonnet N, Martinez A, Marks PM, Cadd VA et al. 2012. A botulinum toxin-derived targeted secretion inhibitor downregulates the GH/IGF1 axis. J. Clin. Investig. 122:3295–306
     [Google Scholar]
  153. 153. 
    Bade S, Rummel A, Reisinger C, Karnath T, Ahnert-Hilger G et al. 2004. Botulinum neurotoxin type D enables cytosolic delivery of enzymatically active cargo proteins to neurones via unfolded translocation intermediates. J. Neurochem. 91:1461–72
     [Google Scholar]
  154. 154. 
    Vazquez-Cintron EJ, Beske PH, Tenezaca L, Tran BQ, Oyler JM et al. 2017. Engineering botulinum neurotoxin C1 as a molecular vehicle for intra-neuronal drug delivery. Sci. Rep. 7:42923
     [Google Scholar]
/content/journals/10.1146/annurev-biochem-013118-111654
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Botulinum and Tetanus Neurotoxins
Annual Review of Biochemistry 88, 811 (2019); https://doi.org/10.1146/annurev-biochem-013118-111654
/content/journals/10.1146/annurev-biochem-013118-111654
/content/journals/10.1146/annurev-biochem-013118-111654
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