Clostridial neurotoxins binding

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. 

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... 

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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