Electric dipole reorientation in the interaction of botulinum neurotoxins with neuronal membranes

Fogolari, Federico; Tosatto, Silvio C. E.; Muraro, Lucia; Montecucco, Cesare

doi:10.1016/j.febslet.2009.06.046

Cited by 17 publications

(12 citation statements)

References 58 publications

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“…Moreover, it has been shown that long-range electrostatic interactions between noncontacting residues of the binding partners can play a critical role in the formation of high-affinity complexes (40,41). Thus, as suggested earlier, gangliosides in anionic microdomains could have a major role in increasing BoNT/B affinity for neuronal membranes through electrostatic interactions involving a positive pole found in the BoNT/B C-terminal domain (30).…”

Section: Discussionmentioning

confidence: 72%

Gangliosides interact with synaptotagmin to form the high-affinity receptor complex for botulinum neurotoxin B

Flores

Ramírez‐Franco

Desplantes

et al. 2019

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

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Botulinum neurotoxin type B (BoNT/B) recognizes nerve terminals by binding to 2 receptor components: a polysialoganglioside, predominantly GT1b, and synaptotagmin 1/2. It is widely thought that BoNT/B initially binds to GT1b then diffuses in the plane of the membrane to interact with synaptotagmin. We have addressed the hypothesis that a GT1b–synaptotagmin cis complex forms the BoNT/B receptor. We identified a consensus glycosphingolipid-binding motif in the extracellular juxtamembrane domain of synaptotagmins 1/2 and confirmed by Langmuir monolayer, surface plasmon resonance, and circular dichroism that GT1b interacts with synaptotagmin peptides containing this sequence, inducing α-helical structure. Molecular modeling and tryptophan fluorescence spectroscopy were consistent with the intertwining of GT1b and synaptotagmin, involving cis interactions between the oligosaccharide and ceramide moieties of GT1b and the juxtamembrane and transmembrane domains of synaptotagmin, respectively. Furthermore, a point mutation on synaptotagmin, located outside of the BoNT/B-binding segment, inhibited GT1b binding and blocked GT1b-induced potentiation of BoNT/B binding to synaptotagmin-expressing cells. Our findings are consistent with a model in which a preassembled GT1b–synaptotagmin complex constitutes the high-affinity BoNT/B receptor.

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Section: Discussionmentioning

confidence: 72%

Gangliosides interact with synaptotagmin to form the high-affinity receptor complex for botulinum neurotoxin B

Flores

Ramírez‐Franco

Desplantes

et al. 2019

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

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“…There is evidence that anionic microdomains of the presynaptic membrane including PSG may orient the electric dipole associated to the BoNT molecules whose positive end is, significantly, located around the PSG binding site. This reorienting effect of the membrane on the approaching BoNT molecule would strongly increase its probability of PSG binding, making it a reaction controlled only by diffusion (Fogolari et al, 2009). …”

Section: Biologymentioning

confidence: 99%

Botulinum Neurotoxins: Biology, Pharmacology, and Toxicology

et al. 2017

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The study of botulinum neurotoxins (BoNT) is rapidly progressing in many aspects. Novel BoNTs are being discovered owing to next generation sequencing, but their biologic and pharmacological properties remain largely unknown. The molecular structure of the large protein complexes that the toxin forms with accessory proteins, which are included in some BoNT type A1 and B1 pharmacological preparations, have been determined. By far the largest effort has been dedicated to the testing and validation of BoNTs as therapeutic agents in an ever increasing number of applications, including pain therapy. BoNT type A1 has been also exploited in a variety of cosmetic treatments, alone or in combination with other agents, and this specific market has reached the size of the one dedicated to the treatment of medical syndromes. The pharmacological properties and mode of action of BoNTs have shed light on general principles of neuronal transport and protein-protein interactions and are stimulating basic science studies. Moreover, the wide array of BoNTs discovered and to be discovered and the production of recombinant BoNTs endowed with specific properties suggest novel uses in therapeutics with increasing disease/symptom specifity. These recent developments are reviewed here to provide an updated picture of the biologic mechanism of action of BoNTs, of their increasing use in pharmacology and in cosmetics, and of their toxicology.

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“…On the other hand, BoNT is dipoles with the positive pole located close to the conserved ganglioside-binding site. This feature leads to a reorientation of the tumbling BoNT molecule while approaching to the membrane in such a way that almost any hit with the ganglioside results in toxin binding (Fogolari, Tosatto, Muraro, & Montecucco, 2009). BoNT/A and BoNT/E bind to SV2, their protein receptor, whereas BoNT/B, BoNT/G, and BoNT/DC bind to the synaptic vesicle protein synaptotagmin I/II (Binz & Rummel, 2009;Dong et al, 2018).…”

Section: Mechanism Of Paralysis Of Nerve Terminals By Tent and Bontsmentioning

confidence: 99%

The role of the single interchains disulfide bond in tetanus and botulinum neurotoxins and the development of antitetanus and antibotulism drugs

Rossetto

Pirazzini

Lista

et al. 2019

Cellular Microbiology

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A large number of bacterial toxins consist of active and cell binding protomers linked by an interchain disulfide bridge. The largest family of such disulfide‐bridged exotoxins is that of the clostridial neurotoxins that consist of two chains and comprise the tetanus neurotoxins causing tetanus and the botulinum neurotoxins causing botulism. Reduction of the interchain disulfide abolishes toxicity, and we discuss the experiments that revealed the role of this structural element in neuronal intoxication. The redox couple thioredoxin reductase–thioredoxin (TrxR‐Trx) was identified as the responsible for reduction of this disulfide occurring on the cytosolic surface of synaptic vesicles. We then discuss the very relevant finding that drugs that inhibit TrxR‐Trx also prevent botulism. On this basis, we propose that ebselen and PX‐12, two TrxR‐Trx specific drugs previously used in clinical trials in humans, satisfy all the requirements for clinical tests aiming at evaluating their capacity to effectively counteract human and animal botulism arising from intestinal toxaemias such as infant botulism.

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Electric dipole reorientation in the interaction of botulinum neurotoxins with neuronal membranes

Cited by 17 publications

References 58 publications

Gangliosides interact with synaptotagmin to form the high-affinity receptor complex for botulinum neurotoxin B

Gangliosides interact with synaptotagmin to form the high-affinity receptor complex for botulinum neurotoxin B

Botulinum Neurotoxins: Biology, Pharmacology, and Toxicology

The role of the single interchains disulfide bond in tetanus and botulinum neurotoxins and the development of antitetanus and antibotulism drugs

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