Structure and function of tetanus and botulinum neurotoxins

Abstract

Tetanus and botulinum neurotoxins are produced by Clostridia and cause the neuroparalytic syndromes of tetanus and botulism. Tetanus neurotoxin acts mainly at the CNS synapse, while the seven botulinum neurotoxins act peripherally. Clostridial neurotoxins share a similar mechanism of cell intoxication: they block the release of neurotransmitters. They are composed of two disulfide-linked polypeptide chains. The larger subunit is responsible for neurospecific binding and cell penetration. Reduction releases the smaller chain in the neuronal cytosol, where it displays its zinc-endopeptidase activity specific for protein components of the neuroexocytosis apparatus. Tetanus neurotoxin and botulinum neurotoxins B, D, F and G recognize specifically VAMP/ synaptobrevin. This integral protein of the synaptic vesicle membrane is cleaved at single peptide bonds, which differ for each neurotoxin. Botulinum A, and E neurotoxins recognize and cleave specifically SNAP-25, a protein of the presynaptic membrane, at two different sites within the carboxyl-terminus. Botulinum neurotoxin type C cleaves syntaxin, another protein of the nerve plasmalemma. These results indicate that VAMP, SNAP-25 and syntaxin play a central role in neuroexocytosis. These three proteins are conserved from yeast to humans and are essential in a variety of docking and fusion events in every cell. Tetanus and botulinum neurotoxins form a new group of zinc-endopeptidases with characteristic sequence, mode of zinc coordination, mechanism of activation and target recognition. They will be of great value in the unravelling of the mechanisms of exocytosis and endocytosis, as they are in the clinical treatment of dystonias.

VAMP2, but Not VAMP3/Cellubrevin, Mediates Insulin-dependent Incorporation of GLUT4 into the Plasma Membrane of L6 Myoblasts

“…Clostridial neurotoxins have been a useful molecular tool to examine the role of SNAREs in the control of exocytic events in various cell systems (Schiavo et al, 1992;Niemann et al, 1994;Jahn et al, 1995;Montecucco and Schiavo, 1995;Tonello et al, 1996). Here we used clostridial tetanus toxin, which inactivates VAMP2 and VAMP3 by cleaving at the bond between amino acids Gln 76 Phe 77 and Gln 63 Phe 64 , respectively (Schiavo et al, 1992).…”

“…There is also strong evidence for the participation of a vesicle (v)-SNARE in this process (Cheatham et al, 1996;Tamori et al, 1996;Chen et al, 1997;Olson et al, 1997;Foran et al, 1999;Millar et al, 1999). The clostridial tetanus and botulinum B or D neurotoxins specifically cleave and inactivate VAMP2 and VAMP3 (Schiavo et al, 1992;Jahn et al, 1995;Montecucco and Schiavo, 1995;Tonello et al, 1996). Introduction of botulinum neurotoxin D into streptolysin O-permeabilized 3T3-L1 adipocytes (Cheatham et al, 1996) reduced the insulin-dependent gain in GLUT4 at the surface of 3T3-L1 adipocytes.…”

Enhancing the Protective Immune Response against Botulism

“…BoNTs are 150-kDa di-chain proteins comprising a 50-kDa light chain (LC) and a 100-kDa heavy chain (HC) linked by a disulfide bond (7,8) (Fig. 1A).…”

Intradetrusor versus suburothelial onabotulinumtoxinA injections for neurogenic detrusor overactivity: a pilot study

“…Botulinum toxin acts on the peripheral nervous system where it is responsible for blockade of acetylcholine release from presynaptic nerve endings. 3 This process results in blockade of the neuromuscular transfer, with a subsequent loss of muscle cell contractility.A further effect of botulinum toxin following administration into the urinary bladder wall is an inhibitory influence on neurotransmitters and receptors mediating sensory neurotransmission. 4,5 The clinical effect of botulinum toxin injection in the treatment of NDO has been established in several studies.…”

“…Botulinum toxin acts on the peripheral nervous system where it is responsible for blockade of acetylcholine release from presynaptic nerve endings. 3 This process results in blockade of the neuromuscular transfer, with a subsequent loss of muscle cell contractility.…”