Specific Membrane Binding of Neurotoxin II Can Facilitate Its Delivery to Acetylcholine Receptor

Lesovoy, Dmitry M.; Bocharov, Eduard V.; Lyukmanova, Ekaterina N.; Kosinsky, Yurij A.; Shulepko, Mikhail A.; Долгих, Д. А.; Kirpichnikov, Mikhaǐl P.; Efremov, Roman G.; Arseniev, Alexander S.

doi:10.1016/j.bpj.2009.07.037

Cited by 35 publications

(22 citation statements)

References 40 publications

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“…Gangliosides in neuronal cell membranes contribute strongly to the negative surface charge as they contribute about 75% of plasma membrane sialic acids (39). 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: 99%

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: 99%

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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“…The amount of negatively charged amino acid is very high in short neurotoxin which is due to the presence of aspartic acid residues in the sequence. Negatively charged aspartic acid and glutamic acid aided appropriate attachment to membrane receptor (Lesovoy et al, 2009). The main function of three-finger proteins is binding to other proteins.…”

Section: Resultsmentioning

confidence: 99%

Functional Characterization of Elapid Venom Toxin Proteins and Related Non-Toxin Proteins of Human through Comparative Analysis

Roly¹,

Ruhullah²,

Tanvir³

et al. 2015

Trends in Bioinformatics

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Snake venom contains a diverse array of pharmacologically active proteins and polypeptides that have led to the development of molecular probes and therapeutic agents. Short neurotoxins and cytotoxins are non-enzymatic polypeptides components of snake venom found only in the venoms of Elapidae (cobras, kraits, mambas, coral snakes and Australian elapids) and Hydrophidae (sea snakes). The three-dimensional structure of short neurotoxins and cytotoxins has three beta stranded loops resembling three-fingers of three-finger protein super family. This protein super family has different family members which are employed in various biological functions. The objective of this study is to search out the amino acid compositional (%) profile, physiochemical properties and functional analysis of three finger toxins present in different elapid snake species to be precise, Bungarus fasciatus, Naja naja and Naja kauthia. We analyzed a total of 23 reference protein sequences representing short neurotoxin and cytotoxin of three elapid snakes and related non-toxin proteins of human in terms of functional analysis, amino acid compositional (%) profile, number of amino acids, molecular weight, theoretical isoelectric point (pI), number of positively charged and negatively charged amino acid residues, instability index and grand average of hydropathy using computational tools. From the result it was found that amino acid composition profile represents that all sequences hold a conserved cysteine amount even as differential amount of different amino acid residues have a particular family pattern. It will also assist to know about involvement in various biological functions those are accountable for the vivid amino acid composition profile of these proteins. This comparative analysis of physicochemical properties would play a significant role in understanding the mechanisms of action of toxins and in the development of lead therapeutic molecules.

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“…For another explanation of the PLA 2 competition with α-Bgt, one should consider the existing model of α-neurotoxin-nAChR interaction: it is accepted that the tip of the toxin central loop is inserted into the receptor at the interfaces between two subunits and the toxin molecule is placed almost equatorially to the extracellular domain of the nAChR. Recently, a possible participation of the membrane in which nAChR is embedded in neurotoxin-receptor interaction was suggested [43, 44]. It was found that a snake venom neurotoxin can bind membrane and this binding can be considered as a first interaction step facilitating the receptor recognition by the toxin.…”

Section: Discussionmentioning

confidence: 99%

Pancreatic and snake venom presynaptically active phospholipases A2 inhibit nicotinic acetylcholine receptors

et al. 2017

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Phospholipases A2 (PLA2s) are enzymes found throughout the animal kingdom. They hydrolyze phospholipids in the sn-2 position producing lysophospholipids and unsaturated fatty acids, agents that can damage membranes. PLA2s from snake venoms have numerous toxic effects, not all of which can be explained by phospholipid hydrolysis, and each enzyme has a specific effect. We have earlier demonstrated the capability of several snake venom PLA2s with different enzymatic, cytotoxic, anticoagulant and antiproliferative properties, to decrease acetylcholine-induced currents in Lymnaea stagnalis neurons, and to compete with α-bungarotoxin for binding to nicotinic acetylcholine receptors (nAChRs) and acetylcholine binding protein. Since nAChRs are implicated in postsynaptic and presynaptic activities, in this work we probe those PLA2s known to have strong presynaptic effects, namely β-bungarotoxin from Bungarus multicinctus and crotoxin from Crotalus durissus terrificus. We also wished to explore whether mammalian PLA2s interact with nAChRs, and have examined non-toxic PLA2 from porcine pancreas. It was found that porcine pancreatic PLA2 and presynaptic β-bungarotoxin blocked currents mediated by nAChRs in Lymnaea neurons with IC50s of 2.5 and 4.8 μM, respectively. Crotoxin competed with radioactive α-bungarotoxin for binding to Torpedo and human α7 nAChRs and to the acetylcholine binding protein. Pancreatic PLA2 interacted similarly with these targets; moreover, it inhibited radioactive α-bungarotoxin binding to the water-soluble extracellular domain of human α9 nAChR, and blocked acetylcholine induced currents in human α9α10 nAChRs heterologously expressed in Xenopus oocytes. These and our earlier results show that all snake PLA2s, including presynaptically active crotoxin and β-bungarotoxin, as well as mammalian pancreatic PLA2, interact with nAChRs. The data obtained suggest that this interaction may be a general property of all PLA2s, which should be proved by further experiments.

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Specific Membrane Binding of Neurotoxin II Can Facilitate Its Delivery to Acetylcholine Receptor

Cited by 35 publications

References 40 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

Functional Characterization of Elapid Venom Toxin Proteins and Related Non-Toxin Proteins of Human through Comparative Analysis

Pancreatic and snake venom presynaptically active phospholipases A2 inhibit nicotinic acetylcholine receptors

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