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.
Similar content being viewed by others
References
Lacy BD, Stevens RC, Sequence homology and structural analysis of the clostridial neurotoxins, J Mol Biol 291, 1091-1104 (1999).
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).
Wagman J, Bateman JB, The behavior of botulinus toxins in the ultracentrifuge, Arch Biochem Biophys 31, 424-30 (1951)
Sakaguchi G, Kozaki S, Ohisi I, Structure and function of bo-tulinum toxins. In Bacterial Protein Toxins, (Academic Press, London, 1984), pp. 435-43.
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 Toxicoil—Toxin Rev 18, 17-34 (1999).
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).
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).
Kitamura M, Sakaguchi S, Sakaguchi G, Significance of 12S toxin of Clostridium botulinum type E, J Bacteriol 98, 1173-8 (1969).
Montecucco C, Schiavo G, Structure and function of tetanus and botulinum neurotoxins, Quarterly Rev Biophys 28, 423-72 (1995).
Simpson LL, Identification of the major steps in botulinum toxin actio, Annu Rev Pharmacol Toxicol 44, 167-93 (2004).
Singh BR, Biomedical and toxico-chemical aspects of botulinum neurotoxins, J Toxicol—Toxin Rev 18, vii-x (1999).
Bell MS, Vermeulen LC, Sperling KB, Pharmacotherapy with bo-tulinum toxin: Harnessing nature's most potent neurotoxin, Rev Ther 20, 1079-91 (2000).
Schengrund C-L, “Multivalent” saccharides: Development of new approaches for inhibiting the effects of glycosphingolipid-binding pathogens, Biochem Pharmacol 65, 699-707 (2003).
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).
Maksymowych AB, Simpson LL, Binding and transcytosis of bo-tulinum neurotoxin by polarized human colon carcinoma cells, J Biol Chem 273, 21950-7 (1998).
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).
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).
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).
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).
van Heyningen WE, Miller PA, The fixation of tetanus toxin by ganglioside, J Gen Microbiol 24, 107-19 (1961).
Lebeda FJ, Olson MA, Secondary structural predictions for the clostridial neurotoxins, Proteins: Struct Funct Genet 20, 293-300 (1994).
Simpson LL, Rapport MM, The binding of botulinum toxin to membrane lipids: Sphingolipids, steroids and fatty acids, J Neurochem 18, 1751-9 (1971).
Simpson LL, Rapport MM, Ganglioside inactivation of botulinum toxin, J Neurochem 18, 1341-3 (1971).
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).
Ochanda JO, Syuto B, Ohishi I, Naiki M, Kubo S, Binding of Clostridium botulinum neurotoxin to gangliosides, J Biochem 100, 27-33 (1986).
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).
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).
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).
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).
Halpern JL, Loftus A, Characterization of the receptor bind-ing domain of tetanus toxin, J Biol Chem 268, 11188-92 (1993).
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).
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).
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).
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).
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).
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).
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)
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).
Yowler BC, Schengrund C-L, Botulinum neurotoxin A changes conformation upon binding to ganglioside GT1b, Biochem 43, 9725-31 (2004).
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).
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).
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).
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).
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).
Simons K, Ikonen E, Functional rafts in cell membranes, Nature 387, 569-72 (1997).
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).
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.
Lee RT, Lee YC, Affinity enhancement by multivalent lectin-carbohydrate interaction, Glycoconj J 17, 543-51 (2000).
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).
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).
Kitamura M, Iwamori M, Nagai Y, Interaction between Clostrid-ium botulinum neurotoxin and gangliosides, Biochim Biophys Acta 628, 328-35 (1980).
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).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
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
Issue Date:
DOI: https://doi.org/10.1023/B:GLYC.0000046271.64647.fd