The high‐affinity binding of Clostridium botulinum type B neurotoxin to synaptotagmin II associated with gangliosides GT1b/GD1a

Nishiki, Tadaaki; Tokuyama, Yoshimi; Kamata, Yoichi; Nemoto, Yasuo; Yoshida, Akira; Sato, Kazuki; Sekiguchi, Mariko; Takahashi, Masami; Kozaki, Shunji

doi:10.1016/0014-5793(95)01471-3

Cited by 213 publications

(164 citation statements)

References 35 publications

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“…Because G T1b gangliosides are present in epithelial cells of the small intestine, this interaction could contribute to adhesion as well. At the neuromuscular junction, synaptic vesicle protein (SV2) and synaptotagmin II (SytII) are the presynaptic protein receptors for BoNT/A1 and BoNT/B, respectively (40)(41)(42), but the relevance of these receptors in the intestine is not clear. We note that the SytII binding site for BoNT/B (43,44) is fully accessible in the context of the 16S PC structure (Fig.…”

Section: Discussionmentioning

confidence: 99%

Molecular assembly of botulinum neurotoxin progenitor complexes

Benefield

Dessain

Shine

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Botulinum neurotoxin (BoNT) is produced by Clostridium botulinum and associates with nontoxic neurotoxin-associated proteins to form high-molecular weight progenitor complexes (PCs). The PCs are required for the oral toxicity of BoNT in the context of food-borne botulism and are thought to protect BoNT from destruction in the gastrointestinal tract and aid in absorption from the gut lumen. The PC can differ in size and protein content depending on the C. botulinum strain. The oral toxicity of the BoNT PC increases as the size of the PC increases, but the molecular architecture of these large complexes and how they contribute to BoNT toxicity have not been elucidated. We have generated 2D images of PCs from strains producing BoNT serotypes A1, B, and E using negative stain electron microscopy and single-particle averaging. The BoNT/A1 and BoNT/B PCs were observed as ovoid-shaped bodies with three appendages, whereas the BoNT/E PC was observed as an ovoid body. Both the BoNT/A1 and BoNT/B PCs showed significant flexibility, and the BoNT/B PC was documented as a heterogeneous population of assembly/disassembly intermediates. We have also determined 3D structures for each serotype using the random conical tilt approach. Crystal structures of the individual proteins were placed into the BoNT/A1 and BoNT/B PC electron density maps to generate unique detailed models of the BoNT PCs. The structures highlight an effective platform that can be engineered for the development of mucosal vaccines and the intestinal absorption of oral biologics.hemagglutinin | nontoxic nonhemagglutinin | sialic acid

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Section: Discussionmentioning

confidence: 99%

Molecular assembly of botulinum neurotoxin progenitor complexes

Benefield

Dessain

Shine

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Each NT recognizes a distinct receptor. Synaptotagmin II associated with ganglioside G T1b has been assigned as protein receptor of BoNT/B and BoNT/G, and synaptic vesicle membrane protein SV2 as receptor of BoNT/A (Nishiki et al, 1994(Nishiki et al, , 1996Rummel et al, 2004a;Dong et al, 2006;Mahrhold et al, 2006). Specific cell surface receptors account for the different sensitivity of cells and animal species to BoNTs and TeNT and play a major role in the subsequent intracellular trafficking.…”

Section: Transcytotic Pathway and Gangliosides: The Case Of Clostridimentioning

confidence: 99%

Bacterial protein toxins and lipids: role in toxin targeting and activity

Geny

Popoff

2006

Biology of the Cell

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All bacterial toxins, which globally are hydrophilic proteins, interact first with their target cells by recognizing a surface receptor, which is either a lipid or a lipid derivative, or another compound but in a lipid environment. Intracellular active toxins follow various trafficking pathways, the sorting of which is greatly dependent on the nature of the receptor, notably lipidic receptor or receptor embedded into a distinct environment such as lipid microdomains. Numerous other toxins act locally on cell membrane. Indeed, phospholipase activity is a common mechanism shared by several membrane‐damaging toxins. In addition, many toxins active intracellularly or on cell membrane modulate host cell phospholipid pathways. Unusually, a few bacterial toxins require a lipid post‐translational modification to be active. Thereby, lipids are obligate partners of bacterial toxins.

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“…Notably, it has the advantages of using as a neuronal acceptor one of the most abundant synaptic vesicle proteins, synaptotagmin II (syt-II), which becomes exposed on nerve terminals upon exocytotic neurotransmitter release. [24][25][26] This study introduces a recombinant core streptavidin (CS)-BoTIM/ B-a novel and versatile moiety for neuronal targeting that combines the uncompromised neurotrophism of the full-length yet atoxic protein coupled to CS, a superb adaptor for covalently attaching to a broad range of biotinylated cargo and viral vectors. Its utility for guided gene transfer is highlighted by a greatly improved transduction of reporter green fluorescent protein (GFP) into neurons as compared with other cell types both in vitro and in vivo.…”

Section: Introductionmentioning

confidence: 99%

Innocuous full-length botulinum neurotoxin targets and promotes the expression of lentiviral vectors in central and autonomic neurons

et al. 2011

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Fragments of botulinum neurotoxin (BoNT) have been explored as potential targeting moieties and carriers of biomolecules into neurons, although with lower binding and translocation efficiency compared with intact proteins. This study exploits a detoxified recombinant form of full-length BoNT/B (BoTIM/B) fused with core streptavidin (CS-BoTIM/B) for lentiviral targeting to central and autonomic neurons. CS-BoTIM/B underwent an activity-dependent entry into cultured spinal cord neurons. Coupling CS-BoTIM/B to biotinylated lentivirus-encoding green fluorescent protein (GFP) endowed considerable neuron selectivity to the vector as evident from the preferential expression of the reporter in neurons co-cultured with skeletal muscle cells. CS-BoTIM/ B-guided lentiviral transduction with the expression of a SNARE protein, SNAP-25 (S25), rendered non-susceptible to proteolysis by three BoNT serotypes, yielded a sizable decrease in cleaved S25 upon exposure of spinal cord neurons to these toxins. This was accompanied by synaptic transmission being spared from blockade by BoNT/A or BoNT/E, reflecting adequate translation and functional competence of recombinant multi-toxin-resistant S25. The augmented neurotropism conveyed on the lentivirus by CS-BoTIM/B was also demonstrated in vivo through enhanced expression of a reporter in intramural ganglionic neurons in the rat trachea, after injection of the targeted GFP-encoding lentivirus. Thus, a novel and realistic prospect for gene therapy of peripheral neuropathies is offered in this study through lentiviral targeting to neurons by CS-BoTIM/B.

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The high‐affinity binding of Clostridium botulinum type B neurotoxin to synaptotagmin II associated with gangliosides G_T1b/G_D1a

Cited by 213 publications

References 35 publications

Molecular assembly of botulinum neurotoxin progenitor complexes

Molecular assembly of botulinum neurotoxin progenitor complexes

Bacterial protein toxins and lipids: role in toxin targeting and activity

Innocuous full-length botulinum neurotoxin targets and promotes the expression of lentiviral vectors in central and autonomic neurons

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