Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.24.69 (botulinum neurotoxin)
 1,901 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The receptor structure of Clostridium botulinum neurotoxin type A was analysed by TLC immunostaining. GQ1b was found to be the most potent receptor, and the neurotoxin also bound to GT1b and GD1a, but not to GM3, GM2, GM1, GD3, GD1b and GT1a. Optimum binding of neurotoxin to the ganglioside appeared in 0.01 M phosphate buffer (pH 7.2) containing 0.2% NaCl. Higher and lower NaCl concentrations diminished neurotoxin binding to the ganglioside. In addition, the neurotoxin was able to bind to free fatty acids. Maximum binding was observed on stearic acid and neurotoxin binding to free fatty acids was not affected by NaCl concentration.
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PMID:TLC immunostaining characterization of Clostridium botulinum type A neurotoxin binding to gangliosides and free fatty acids. 370 10

The effect of gangliosides on Clostridium botulinum type A neurotoxin was examined in terms of detoxification. The molar concentrations of gangliosides necessary to detoxify 50% of 1 M Cl. botulinum neurotoxin were as follows: GM1, 2073; GM2, 2439; GM3, 6098; GD1a, 610; GD1b, 488; GT1a, 829; GT1b, 6 and GQ1b, 27. Inhibition by gangliosides of the neurotoxin binding to synaptosomes showed that GT1b was highly effective, but the others were not. Low-temperature treatment inhibited the detoxification of neurotoxin by GT1b and the binding of 125I-labelled neurotoxin to the synaptosome fraction. 125I-labelled neurotoxin was mixed with GM1 or GT1b and their molecular size was estimated by sucrose-density-gradient centrifugation. When 125I-labelled neurotoxin was incubated with GM1, a single radioactive peak having a sedimentation coefficient of 7.3 S appeared. When incubated with GT1b, however, 125I-labelled neurotoxin gave three peaks having sedimentation coefficients 14, 10 and 7.3 S, respectively. The present results indicated that the location and the number of sialic acids in ganglioside molecules are of significance in the detoxification and the binding of Cl. botulinum neurotoxin with ganglioside molecules.
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PMID:Interaction between Clostridium botulinum neurotoxin and gangliosides. 676

The high toxicity of clostridial neurotoxins primarily results from their specific binding and uptake into neurons. At motor neurons, the seven botulinum neurotoxin serotypes A-G (BoNT/A-G) inhibit acetylcholine release, leading to flaccid paralysis, while tetanus neurotoxin blocks neurotransmitter release in inhibitory neurons, resulting in spastic paralysis. Uptake of BoNT/A, B, E and G requires a dual interaction with gangliosides and the synaptic vesicle (SV) proteins synaptotagmin or SV2, whereas little is known about the entry mechanisms of the remaining serotypes. Here, we demonstrate that BoNT/F as wells depends on the presence of gangliosides, by employing phrenic nerve hemidiaphragm preparations derived from mice expressing GM3, GM2, GM1 and GD1a or only GM3. Subsequent site-directed mutagenesis based on homology models identified the ganglioside binding site at a conserved location in BoNT/E and F. Using the mice phrenic nerve hemidiaphragm assay as a physiological model system, cross-competition of full-length neurotoxin binding by recombinant binding fragments, plus accelerated neurotoxin uptake upon increased electrical stimulation, indicate that BoNT/F employs SV2 as protein receptor, whereas BoNT/C and D utilise different SV receptor structures. The co-precipitation of SV2A, B and C from Triton-solubilised SVs by BoNT/F underlines this conclusion.
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PMID:Botulinum neurotoxins C, E and F bind gangliosides via a conserved binding site prior to stimulation-dependent uptake with botulinum neurotoxin F utilising the three isoforms of SV2 as second receptor. 1965 Aug 74

The extraordinarily high toxicity of botulinum neurotoxins primarily results from their specific binding and uptake into neurons. At motor neurons, the seven BoNT (botulinum neurotoxin) serotypes A-G inhibit acetylcholine release leading to flaccid paralysis. Uptake of BoNT/A, B, E, F and G requires a dual interaction with gangliosides and the synaptic vesicle proteins synaptotagmin or SV2 (synaptic vesicle glycoprotein 2), whereas little is known about the cell entry mechanisms of the serotypes C and D, which display the lowest amino acid sequence identity compared with the other five serotypes. In the present study we demonstrate that the neurotoxicity of BoNT/D depends on the presence of gangliosides by employing phrenic nerve hemidiaphragm preparations derived from mice expressing the gangliosides GM3, GM2, GM1 and GD1a, or only GM3 [a description of our use of ganglioside nomenclature is given in Svennerholm (1994) Prog. Brain Res. 101, XI-XIV]. High-resolution crystal structures of the 50 kDa cell-binding domain of BoNT/D alone and in complex with sialic acid, as well as biological analyses of single-site BoNT/D mutants identified two carbohydrate-binding sites. One site is located at a position previously identified in BoNT/A, B, E, F and G, but is lacking the conserved SXWY motif. The other site, co-ordinating one molecule of sialic acid, resembles the second ganglioside-binding pocket (the sialic-acid-binding site) of TeNT (tetanus neurotoxin).
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PMID:Botulinum neurotoxin serotype D attacks neurons via two carbohydrate-binding sites in a ganglioside-dependent manner. 2070 66