Structure Tetanus neurotoxin

Ledoux, D.N., Be, X.H. and Singh, B.R., Quaternary structure of botulinum and tetanus neurotoxins as probed by chemical cross-linking and native gel electrophoresis, Toxicon, 32, 1095-1104, 1994. 

Breidenbach MA, Brunger AT (2005a) 2.3 A crystal structure of tetanus neurotoxin light chain. Biochemistry 44 7450-7... 

Among the toxins with intracellular targets, we will focus mostly on the botulinum neurotoxins although some references will be made to tetanus neurotoxin because of the structural and functional relationships between tetanus and botulinum neurotoxins. While... 

Table 2. Secondary structure estimation of botulinum and tetanus neurotoxins as analyzed by circular dichroism under physiological pH conditions (Singh et al., 1990 Singh and DasGupta, 1989b)...

Figure 5. Primary amino acid sequence of type A botulinum neurotoxin and tetanus neurotoxin showing possible leucine zipper-like structures. Residues with asterisk( ) mark offset the zipper scheme by one residue.

If botulinum and tetanus neurotoxins exist as dimer or trimer/tetramer in aqueous solutions (Fig. 7), what could be the physiological role of such structures The observation could be relevant to explain the behavior of botulinum neurotoxin with mouse phrenic hemidiaphragm at different concentrations (Bandyopadhyay, 1987 Maisey et al., 1988), Because both the neurotoxins exist in more than one oligomeric form, it is possible that these oligomeric forms are in equilibrium with each other (Fig. 7), and this equilibrium could be altered in different conditions such as in low pH and upon interaction with membranes. A model of oligomeric channel is shown in Figure 8 assuming a trimeric form of botulinum neurotoxin. 

Figure 7. Schematic representation of oligomeric structure of type Abotulinum and tetanus neurotoxins. Based on results in Ledoux et al. (1994) and modified after Singh (1993), it is assumed that botulinum neurotoxin exists as trimer and tetramer whereas tetanus neurotoxin exists as dimer and trimer. The arrows indicate possible interconversion between two oligomeric form. The shaded areas indicate the location of amphiphilic/trans-membrane region of the monomeric units.

Figure 8. Schematic model of an oligomeric membrane channel structure by botulinum or tetanus neurotoxin. The model shows a trimer of the neurotoxin with smaller cylinders representing light chain whereas larger lobe representing heavy chain.

Singh, B. R., 1993, Structure-function relationship of botulinum and tetanus neurotoxins. In Botulinum and Tetanus Neurotoxins Neurotransmission and Biomedical Aspects (B. R. DasGupta, ed.). Plenum Press, pp. 377-392. 

Singh, B. R., Fuller, M. P. and Schiavo, G., 1990, Molecular structure of tetanus neurotoxin as revealed by Fourier transform infrared and circular dichroic spectroscopy. Biophysical Chem. 36, 155-166. 

Singh, B. R., Ledoux, D. N. and Fu, F.-N., 1994, An analysis of the protein structure of botulinum and tetanus neurotoxins to understand molecular basis of membrane channel formation. In Advances in Venom and Toxin Research (Tan, N. H., Oo, S. L., Thambyrajah, V. and Azila, N.. eds.), Malaysian Society on Toxinology, Kuala Lumpur, pp. 103-108. 

Montecucco C, Schiavo G (1995) Structure and function of tetanus and botulinum neurotoxins. Q Rev Biophys 28 423-72... 

Pellizzari R, Rossetto O, Lozzi L, Giovedi S, Johnson E et al. (1996) Structural determinants of the specificity for synaptic vesicle-associated membrane protein/synaptobrevin of tetanus and botulinum type B and G neurotoxins. J Biol Chem 271 20353-8 Pellizzari R, Mason S, Shone CC, Montecucco C (1997) The interaction of synaptic vesicle-associated membrane protein/synaptobrevin with botulinum neurotoxins D and F. FEBS Lett 409 339 12... 

Yamasaki S, Hu Y, Binz T, Kalkuhl A, Kurazono H et al. (1994) Synaptobrevin/vesicle-assodated membrane protein (VAMP) of aplysia califomica structure and proteolysis by tetanus toxin and botubnal neurotoxins type D and F. Proc Natl Acad Sci U S A 91 4688-92... 

Future important discoveries will be the identification of the neuron-specific receptors of CNTs and of the mode of internalization and membrane translocation of the neurotoxins. Another important line of research is aimed at finding specific inhibitors of these metallo-proteinases. Inhibitors which can cross the neuronal plasmalemma into the cytosol would be potential therapeutic agents in the treatment of tetanus and botulism. The modification of BoNTs to prolong their life time inside the NMJs would be an important research goal to improve the treatment of dystonias. The determination of the three-dimensional structure of these neurotoxins will greatly accelerate the research on these fronts. 

Kriegistein KG, Henschen AH, Weller U, Habermann E (1991) Limited proteolysis of tetanus toxin. In Eur. J. Biochem. 202 41 -51 Lebeda FJ, Olson MA (1994) Secondary structural predictions for the clostridial neurotoxins. Proteins 20 293-300... 

Matsuda M, Lei DL, Sugimoto N, Ozutsumi K, OkabeT (1989) Isolation, purification and characterization of fragment B, the NH2-terminal half of the heavy chain of tetanus toxin. In Infect. Immun. 57 3588-93 Matthews BW (1988) Structural basis of the action of thermolysin and related zinc peptidases.In Acc. Chem. Res. 21 333-40 Mclnnes C, Dolly JO (1990) Ca -dependent noradrenaline release from perme-abilised PC 12 cells is blocked by botulinum neurotoxin A or its light chain. In FEBS Lett. 261 323-6... 

The family of structural genes for the clostridial neurotoxins is unrestricted in its location, being both chromosomal and extrachromosomal. The structural gene for tetanus toxin is on a plasmid, as is probably the structural gene for botulinum toxin serotype G.15 The structural genes for botulinum toxin serotypes C and D are found on bacteriophages.1017 The remainder are believed to be chromosomal in location, but this is not definitely proven. 

DasGupta, B. R., 1989, The structure of botulinum neurotoxin. In Botulinum Neurotoxin and Tetanus Toxin (Simpson, L. L., ed.). Academic Press, SanDiego. pp. 53-67. 

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