Neurotoxins clostridial

Clostridial neurotoxins are bacterial protein toxins that consist of a heavy and a light chain connected by a disulfide bond and non-covalent interactions. They... 

The light chains of the clostridial neurotoxins are metalloproteases with exclusive specificity for neuronal SNAREs. TeNT, BoNTs B,D,F, and G cleave synapto-brevin, BoNTs A and E SNAP-25, and BoNT/Cl syntaxin, and to a lesser extent also SNAP-25. Cleavage of any of the SNAREs causes complete and irreversible block of synaptic transmission. 

Clonal Selection Clostridial Neurotoxins Clostridium Botulinum Toxin Clotting CNTF... 

Classical bacterial exotoxins, such as diphtheria toxin, cholera toxin, clostridial neurotoxins, and the anthrax toxins are enzymes that modify their substrates within the cytosol of mammalian cells. To reach the cytosol, these toxins must first bind to different cell-surface receptors and become subsequently internalized by the cells. To this end, many bacterial exotoxins contain two functionally different domains. The binding (B-) domain binds to a cellular receptor and mediates uptake of the enzymatically active (A-) domain into the cytosol, where the A-domain modifies its specific substrate (see Figure 1). Thus, three important properties characterize the mode of action for any AB-type toxin selectivity, specificity, and potency. Because of their selectivity toward certain cell types and their specificity for cellular substrate molecules, most of the individual exotoxins are associated with a distinct disease. Because of their enzymatic nature, placement of very few A-domain molecules in the cytosol will normally cause a cytopathic effect. Therefore, bacterial AB-type exotoxins which include the potent neurotoxins from Clostridium tetani and C. botulinum are the most toxic substances known today. However, the individual AB-type toxins can greatly vary in terms of subunit composition and enzyme activity (see Table 2). 

The absolute neurospecificity of clostridial neurotoxins, and the ability of TeNT to undergo axonal retrograde transport, make them ideal tools to study endocyto-sis and sorting at the synapse, and of retro-axonal transport both in vitro and in vivo (reviewed in Deinhardt and Schiavo 2005). These processes, which are still poorly understood at the molecular level, represent an exciting area of application for clostridial neurotoxins and their binding fragments. 

Breidenbach MA, Brunger AT (2005b) New insights into clostridial neurotoxin-SNARE interactions. Trends Mol Med 11 377-81... 

Minton NP (1995) Molecular genetics of clostridial neurotoxins. Curr Top Microbiol Immunol 195 161-94... 

Montecucco C, Schiavo G, Tugnoli V, de Grandis D (1996) Botulinum neurotoxins mechanism of action and therapeutic applications. Mol Med Today 2 418-24 Montecucco C, Rossetto O, Schiavo G (2004) Presynaptic receptor arrays for clostridial neurotoxins. Trends Microbiol 12 442-6... 

Niemann H (1991) Molecular biology of clostridial neurotoxins. In Alouf J, Freer J (eds) A source-book of bacterial protein toxins. Academic Press, London, pp 303 18 Nishiki T, Tokuyama Y, Kamata Y, Nemoto Y, Yoshida A et al. (1996) The high-affinity binding of Clostridium botulinum type b neurotoxin to synaptotagmin ii associated with gangliosides gtlb/gdla. FEBS Lett 378 253-7... 

Rizzoli SO, Betz WJ (2005) Synaptic vesicle pools. Nat Rev Neurosci 6 57-69 Rossetto O, Montecucco C (2004) Clostridial neurotoxins. In Proft C (ed) Microbial toxins, molecular and cellular biology. Horizon Scientific Press, Norfolk, UK, pp 149-78 Rossetto O, Montecucco C (2007) Peculiar binding of botulinum neurotoxins. ACS Chem Biol 2 96-8... 

Simpson LL, Coffield JA, Bakry N (1994) Inhibition of vacuolar adenosine triphosphatase antagonizes the effects of clostridial neurotoxins but not phospholipase A2 neurotoxins. J Pharmacol Exp Ther 269 256-62... 

Williamson LC, Neale EA (1998) Syntaxin and 25-kDa synaptosomal-associated protein differential effects of botulinum neurotoxins Cl and A on neuronal survival. J Neurosci Res 52 569-83 Williamson LC, Halpem JL, Montecucco C, Brown JE, Neale EA (1996) Clostridial neurotoxins and substrate proteolysis in intact neurons botulinum neurotoxin C acts on synaptosomal-associated protein of 25 kDa. J Biol Chem 271 7694-9 Wilson HI, Nicholson GM, Tyler MI, Howden ME (1995) Induction of giant miniature end-plate potentials during blockade of neuromuscular transmission by textilotoxin. Naunyn Schmiede-bergs Arch Pharmacol 352 79-87... 

Graham ME, Fisher RJ, Burgoyne RD (2000) Measurement of exocytosis by amperometry in adrenal chromaffin cells effects of clostridial neurotoxins and activation of protein kinase C on fusion pore kinetics. Biochimie 82 469-79... 

Lebeda, F. J Umland, T. C Sax, M. Olson, M. A. (1998). Accuracy of secondary structure and solvent accessibility predictions for a clostridial neurotoxin C-fragment. J Protein Chem 17,311-8. 

Neurotoxins, such as the clostridial neurotoxins responsible for tetanus and botulism. These are metallo-proteases that enter nerve cells and block neurotransmitter release via zinc-dependent cleavage of protein components of the neuroexocytosis apparatus. 

Habermann, E., Dreyer, F. (1986). Clostridial neurotoxins handling and action at the cellular and molecular level. Curr. Top. Microbiol. Immunol. 129 93-179. 

FHatheway CL (1990) Bacterial Sources of Clostridial Neurotoxins. In Botulinum Neurotoxin and Tetanus Toxin. (Simpson, LL, ed) pp 3-24, San Diego Academic Press... 

The extreme toxicity of clostridial neurotoxins (CNTs) derives from their absolute neurospecificity as well as from catalytic activity. TeTx and BoNTs bind specifically to the neuromuscular junction (NMJ) of motor neurons. The identity of the receptor(s) on the presynaptic membrane is unknown, but their extreme toxicity suggests that the binding affinity to the cognate receptor must be very high. The receptor-bound toxin is internalized at the presynaptic membrane of the NMJ and gains access to the neuronal cytosol. Here it blocks the release of acetylcholine (ACh), causing a flaccid paralysis (Simpson,... 

Fig. 2. Structure and active site of clostridial neurotoxins. The upper panel shows the structure of CNTs, and the segments that show significant homology between the different serotypes are in black (Minton, 1995). The highest homology is shown by a short segment corresponding to the amino acid residues 216-244 in TeTx. This segment contains the zinc-binding motif of metallo-proteinases (zincins) and it is dissimilar to the consensus sequence of the metzincin metallo-proteinase family (Jiang and Bond, 1992)...

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