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Glycosphingolipids—Sweets for botulinum neurotoxin

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Abstract

A number of viruses, bacteria, and bacterial toxins can only act on cells that express the appropriate glycosphingolipids (GSLs) on the outer surface of their plasma membranes. An example of this dependency is provided by botulinum neurotoxin (BoNT) which is synthesized by Clostridium botulinum and inhibits neurotransmission at the neuromuscular junction by catalyzing hydrolysis of a SNARE protein, thereby inducing a flaccid paralysis. Haemagglutinin components of progenitor forms of BoNT mediate its adherence to glycosphingolipids (GSLs) on intestinal epithelial cells while the cellular activity of most isolated serotypes requires the presence of certain gangliosides, especially those of the Gg1b family. This review discusses available information about the identity and the roles of GSLs in the activity of BoNT. Observations that serotypes A-F of BoNT require gangliosides for optimum activity (serotype G apparently does not), permits the hypothesis that it should be possible to develop an antagonist of this interaction thereby inhibiting/reducing its effect. Published in 2004.

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References

  1. Lacy BD, Stevens RC, Sequence homology and structural analysis of the clostridial neurotoxins, J Mol Biol 291, 1091-1104 (1999).

    Article  PubMed  CAS  Google Scholar 

  2. Lalli G, Herreros J, Osborne SL, Montecucco C, Rossetto O, Schiavo G, Functional characterization of tetanus and botulinum neurotoxins binding domains, J Cell Sci 112, 2715-24 (1999).

    PubMed  CAS  Google Scholar 

  3. Wagman J, Bateman JB, The behavior of botulinus toxins in the ultracentrifuge, Arch Biochem Biophys 31, 424-30 (1951)

    Article  CAS  Google Scholar 

  4. Sakaguchi G, Kozaki S, Ohisi I, Structure and function of bo-tulinum toxins. In Bacterial Protein Toxins, (Academic Press, London, 1984), pp. 435-43.

    Google Scholar 

  5. Oguma K, Inoue K, Fujinaga Y, Yokota K, Watanabe T, Ohyama T, Takeshi K, Inoue K,Structure and function of Clostridium botulinum progenitor toxin, J ToxicoilToxin Rev 18, 17-34 (1999).

    CAS  Google Scholar 

  6. Fujinaga Y, Inoue K, Watanabe S, Yokota K, Hirai Y, Nagamachi E, Oguma K, 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, Microbiol 143, 3841-7 (1997).

    Article  CAS  Google Scholar 

  7. Heckly RJ, Hildebrand GJ, Lamanna C, On the size of the toxin particle passing the intestinal barrier in botulism, J Exp Med 111, 745-59 (1960).

    Article  PubMed  CAS  Google Scholar 

  8. Kitamura M, Sakaguchi S, Sakaguchi G, Significance of 12S toxin of Clostridium botulinum type E, J Bacteriol 98, 1173-8 (1969).

    PubMed  CAS  Google Scholar 

  9. Montecucco C, Schiavo G, Structure and function of tetanus and botulinum neurotoxins, Quarterly Rev Biophys 28, 423-72 (1995).

    Article  CAS  Google Scholar 

  10. Simpson LL, Identification of the major steps in botulinum toxin actio, Annu Rev Pharmacol Toxicol 44, 167-93 (2004).

    Article  PubMed  CAS  Google Scholar 

  11. Singh BR, Biomedical and toxico-chemical aspects of botulinum neurotoxins, J Toxicol—Toxin Rev 18, vii-x (1999).

    Google Scholar 

  12. Bell MS, Vermeulen LC, Sperling KB, Pharmacotherapy with bo-tulinum toxin: Harnessing nature's most potent neurotoxin, Rev Ther 20, 1079-91 (2000).

    CAS  Google Scholar 

  13. Schengrund C-L, “Multivalent” saccharides: Development of new approaches for inhibiting the effects of glycosphingolipid-binding pathogens, Biochem Pharmacol 65, 699-707 (2003).

    Article  PubMed  CAS  Google Scholar 

  14. Rummel A, Karnath T, Henke T, Bigalke H, Binz T, Synaptotag-mins I and II act as nerve cell receptors for botulinum neurotoxin G, J Biol Chem(in press, April 30, 2004).

  15. Maksymowych AB, Simpson LL, Binding and transcytosis of bo-tulinum neurotoxin by polarized human colon carcinoma cells, J Biol Chem 273, 21950-7 (1998).

    Article  PubMed  CAS  Google Scholar 

  16. Fujinaga Y, Inoue K, Watarai S, Sakaguchi Y, Arimitsu H, Lee J-C, Jin Y, Matsumura T, Kabumoto Y, Watanabe T, Ohyama T, Nishikawa A, Oguma K, Molecular characterization of binding subcomponents of Clostridium botulinum type C progenitor toxin for intestinal epithelial cells and erythrocytes, Microbiol 150, 1529-38 (2004).

    Article  CAS  Google Scholar 

  17. Inoue K, Fujinaga Y, Honke K, Arimitsu H, Mahmut N, Sakaguchi Y, Ohyama T, Watanabe T, Inoue K, Oguma K, Clostridium botulinum type A haemagglutinin-positive progenitor toxin (HA-PTX)binds to oligosaccharides containing Gal 1-4GlcNAc through one subcomponent of haemagglutinin (HA1), Microbiol 147, 811-9 (2001).

    CAS  Google Scholar 

  18. Fujinaga Y, Inoue K, Nomura T, Sasaki J, Marvaud JC, Popoff MR, Kozaki S, Oguma K, Identification and characterization of functional subunits of Clostridium botulinum type A progenitor toxin involved in binding to intestinal microvilli and erythrocytes, FEBS Lett 467, 179-83 (2000).

    Article  PubMed  CAS  Google Scholar 

  19. Inoue K, Sobhany M, Transue TR, Oguma K, Pedersen LC, Negishi M, Structural analysis by X-ray crystallography and calorimetry of a haemagglutinin component (HA1) of the progen-itor toxin from Clostridium botulinum, Microbiol 149, 3361-70 (2003).

    Article  CAS  Google Scholar 

  20. van Heyningen WE, Miller PA, The fixation of tetanus toxin by ganglioside, J Gen Microbiol 24, 107-19 (1961).

    PubMed  CAS  Google Scholar 

  21. Lebeda FJ, Olson MA, Secondary structural predictions for the clostridial neurotoxins, Proteins: Struct Funct Genet 20, 293-300 (1994).

    Article  CAS  Google Scholar 

  22. Simpson LL, Rapport MM, The binding of botulinum toxin to membrane lipids: Sphingolipids, steroids and fatty acids, J Neurochem 18, 1751-9 (1971).

    PubMed  CAS  Google Scholar 

  23. Simpson LL, Rapport MM, Ganglioside inactivation of botulinum toxin, J Neurochem 18, 1341-3 (1971).

    PubMed  CAS  Google Scholar 

  24. Takamizawa K, Iwamori M, Kozaki S, Sakaguchi G, Tanaka R, Takayama H, Nagai Y, TLC immunostaining characterization of Clostridium botulinum type A neurotoxin binding to gangliosides and free fatty acids, FEBS Lett 201, 229-32 (1986).

    Article  PubMed  CAS  Google Scholar 

  25. Ochanda JO, Syuto B, Ohishi I, Naiki M, Kubo S, Binding of Clostridium botulinum neurotoxin to gangliosides, J Biochem 100, 27-33 (1986).

    PubMed  CAS  Google Scholar 

  26. Kitamura M, Takamiya K, Aizawa S, Furukawa K, Furukawa K, Gangliosides are the binding substances in neural cells for tetanus and botulinum toxins in mice, Biochim Biophys Acta 1441, 1-3 (1999).

    PubMed  CAS  Google Scholar 

  27. Bullens RWM, O'Hanloon GM, Wagner E, Molenaar PC, Furukawa K, Furukawa K, Plomp JJ, Willison HJ, Complex gangliosides at the neuromuscular junction are membrane re-ceptors for autoantibodies and botulinum neurotoxin but re-dundant for normal synaptic function, J Neurosci 22, 6876-84 (2002).

    PubMed  CAS  Google Scholar 

  28. Yowler BC, Kensinger RD, Schengrund C-L, Botulinum neuro-toxin A activity is dependent upon the presence of specific gan-gliosides in neuroblastoma cells expressing synaptotagmin I, J Biol Chem 227, 32815-9 (2002).

    Article  Google Scholar 

  29. Morris NP, Consiglio E, Kohn LS, Habig WH, Hardegree MC, Helting TB, Interaction of fragments B and C of tetanus toxin with neural and thyroid membranes and with gangliosides, J Biol Chem 255, 6071-6 (1980).

    PubMed  CAS  Google Scholar 

  30. Halpern JL, Loftus A, Characterization of the receptor bind-ing domain of tetanus toxin, J Biol Chem 268, 11188-92 (1993).

    PubMed  CAS  Google Scholar 

  31. Umland TC, Wingert LM, Swaminathan S, Furey WF, Schmidt JJ, Sax M, Structure of the receptor binding fragment of Hc of tetanus neurotoxin, Nat Struct Biol 4, 788-92 (1997).

    Article  PubMed  CAS  Google Scholar 

  32. Kamata Y, Kozaki S, Sakaguchi G, Iwamori M, Nagai Y, Evidence for direct binding of Clostridium botulinum type E derivative toxin and its fragments to gangliosides and free fatty acids, Biochem Biophys Res Commun 140, 1015-9 (1986).

    Article  PubMed  CAS  Google Scholar 

  33. Gimenez JA, DasGupta BR, Botulinum type Aneurotoxin digested with pepsin yields 132, 97, 72, 45 and 18 kD fragments, J Protein Chem 12, 351-63 (1993).

    Article  PubMed  CAS  Google Scholar 

  34. Lacy DB, Tepp W, Cohen AC, DasGupta BR, Stevens RC, Crystal structure of botulinum neurotoxin type A and implications for toxicity, Nat Struct Biol 5, 898-902 (1998).

    Article  PubMed  CAS  Google Scholar 

  35. Swaminathan S, Easwaramoorthy S, Structural analysis of the cat-alytic and binding sites of Clostridium botulinum neurotoxin B, Nat Struct Biol 7, 693-9 (2000).

    Article  PubMed  CAS  Google Scholar 

  36. Rummel A, Bade S, Alves J, Bigalke H, Binz T, Two carbohydrate binding sites in the Hcc-domain of tetanus neurotoxin are required for toxicity, J Mol Biol 326, 835-47 (2003).

    Article  PubMed  CAS  Google Scholar 

  37. Rummel A, Mahrhold S, Bigalke H, Binz T, The Hcc-domain of botulinum neurotoxins A and B exhibits a singular ganglioside binding site displaying serotype specific carbohydrate interaction, Molec Microbiol 51, 631-43 (2004)

    Article  CAS  Google Scholar 

  38. Schengrund C-L, Ringler NJ, DasGupta BR, Adherence of bo-tulinum and tetanus neurotoxins to ganglioside GT1b and deriva-tives thereof, J Neurochem 57, 1024-32 (1991).

    PubMed  CAS  Google Scholar 

  39. Yowler BC, Schengrund C-L, Botulinum neurotoxin A changes conformation upon binding to ganglioside GT1b, Biochem 43, 9725-31 (2004).

    Article  CAS  Google Scholar 

  40. Schengrund C-L, DasGupta BR, Ringler NJ, Ganglioside GD3 en-hances adherence of botulinum and tetanus neurotoxins to bovine brain synapsin I, Neurosci Lett 158, 159-62 (1993).

    Article  PubMed  CAS  Google Scholar 

  41. Schengrund C-L, DasGupta BR, Hughes CA, Ringler NJ, Ganglioside-induced adherence of botulinum and tetanus neuro-toxins to adducin, J Neurochem 66, 2556-61 (1996).

    Article  PubMed  CAS  Google Scholar 

  42. Lazarovici P, Yanai P, Yavin E, Molecular interactions between micellar polysialogangliosides and affinity-purified tetanotoxins in aqueous solution, J Biol Chem 262, 2645-51 (1987).

    PubMed  CAS  Google Scholar 

  43. Winter A, Ulrich WP, Wetterich F, Weller U, Galla HJ, Ganglio-sides in phospholipid bilayer membranes: Interaction with tetanus toxin, Chem Phys Lipids 81, 21-34 (1996).

    Article  PubMed  CAS  Google Scholar 

  44. Herreros J, Ng T, Schiavo G, Lipid rafts act as specialized domains for tetanus toxin binding and internalization into neurons, Mol Biol Cell 12, 2947-60 (2001).

    PubMed  CAS  Google Scholar 

  45. Simons K, Ikonen E, Functional rafts in cell membranes, Nature 387, 569-72 (1997).

    Article  PubMed  CAS  Google Scholar 

  46. Kozaki S, Kamata Y, Watarai S, Nishiki T, Mochida S, Gan-glioside GT1b as a complementary receptor component for Clostridium botulinum neurotoxins, Microb Pathol 25, 91-9 (1998).

    Article  CAS  Google Scholar 

  47. Nishiki T, Tokuyama Y, Kamata Y, Nemoto Y, Yoshida A, Sato K, Sekiguchi M, Takahashi M, Kozaki S, The high-affinity binding of Clostridium botulinum type B neurotoxin to synaptotagmin II associated with gangliosides GT1b/GD1a, FEBS Lett 378, 253-7.

  48. Lee RT, Lee YC, Affinity enhancement by multivalent lectin-carbohydrate interaction, Glycoconj J 17, 543-51 (2000).

    Article  PubMed  CAS  Google Scholar 

  49. Schwarzmann G, Mraz W, Sattler J, Schindler R, Wiegandt H, Comparison of the interaction of mono-and oligovalent ligands with cholera toxin. Demonstration of aggregate formation at low concentrations, Hoppe Seylers Z Physiol Chem 359, 1277-86 (1978).

    PubMed  CAS  Google Scholar 

  50. Schengrund C-L, Ringler NJ, Binding of Vibrio cholera toxin and the heat-labile enterotoxin of Escherichia coli to GM1, derivatives of GM1, and non-lipid oligosaccharide polyvalent ligands, J Biol Chem 264, 13233-7 (1989).

    PubMed  CAS  Google Scholar 

  51. Kitamura M, Iwamori M, Nagai Y, Interaction between Clostrid-ium botulinum neurotoxin and gangliosides, Biochim Biophys Acta 628, 328-35 (1980).

    PubMed  CAS  Google Scholar 

  52. Agui T, Syuto B, Oguma K, Iida H, Kubo S, The structural relation between the antigenic determinants to monoclonal antibodies and binding sites to rat brain synaptosomes and GT1b ganglioside in Clostridium botulinum type C neurotoxin, J Biochem (Tokyo) 97, 213-8 (1985).

    PubMed  CAS  Google Scholar 

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Correspondence to Cara-Lynne Schengrund.

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Yowler, B.C., Schengrund, CL. Glycosphingolipids—Sweets for botulinum neurotoxin. Glycoconj J 21, 287–293 (2004). https://doi.org/10.1023/B:GLYC.0000046271.64647.fd

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