Mechanism of action of tetanus and botulinum neurotoxins

Abstract

The clostridial neurotoxins responsible for tetanus and botulism are metallo-proteases that enter nerve cells and block neurotransmitter release via zinc-dependent cleavage of protein components of the neuroexocytosis apparatus. Tetanus neurotoxin (TeNT) binds to the presynaptic membrane of the neuromuscular junction and is internalized and transported retroaxonally to the spinal cord. Whilst TeNT causes spastic paralysis by acting on the spinal inhibitory interneurons, the seven serotypes of botulinum neurotoxins (BoNT) induce a flaccid paralysis because they intoxicate the neuromuscular junction. TeNT and BoNT serotypes B, D, F and G specifically cleave VAMP/synaptobrevin, a membrane protein of small synaptic vesicles, at different single peptide bonds. Proteins of the presynaptic membrane are specifically attacked by the other BoNTs: serotypes A and E cleave SNAP-25 at two different sites located within the carboxyl terminus, whereas the specific target of serotype C is syntaxin.

Arrest of Mycobacterial Phagosome Maturation Is Caused by a Block in Vesicle Fusion between Stages Controlled by rab5 and rab7

“…Although it is not known whether and how mycobacteria modulate the membrane constituents of the phagosome to block phagosome mat- uration events, molecules controlling vesicular trafficking have been implicated as targets for several toxins from different bacterial pathogens. For example, Clostridium tetani, Clostridium botulinum, and Helicobacter pylori produce toxins that affect or change vesicle fusion capacity (55,56). Furthermore, bacterial toxins affecting small GTP-binding proteins via ADPribosylation or transfer of glucose from UDP-glucose have been identified in C. botulinum (57,58) and Clostridium difficile (59).…”

Similar effects of α‐ and β‐SNAP on Ca 2+‐regulated exocytosis

“…Key proteins that act in Ca2+-regulated exocytosis in neurons and endocrine cells include the vesicle proteins synaptotagmin [1] and VAMP/synaptobrevin [2,3], the plasma membrane proteins syntaxin [4] and SNAP-25 [5] and, in addition, the soluble N-ethylmaleimide-sensitive fusion protein (NSF) [16] and soluble NSF-attachment proteins (c~-, 13-and ySNAPs) [7] Functional evidence for the importance of the membrane proteins has come from their sensitivity to the specific proteolytic actions of clostridial neurotoxins [8,9] and/or genetic analysis in mice and Drosophila [10][11][12]. The soluble factors NSF and SNAP were found to interact, in a 20S complex, with the neurotoxin substrates leading to them being designated as SNAP-receptors (SNARE) [13,14].…”

Botulinum neurotoxin light chains inhibit both Ca2+‐induced and GTP analogue‐induced catecholamine release from permeabilised adrenal chromaffin cells

“…The synaptic vesicle protein known either as synaptobrevin or VAMP [4,5] is a substrate for tetanus toxin and for botulinum neurotoxins B, D, F and G [2,3]. SNAP-25 and syntaxin were originally identified as presynaptic membrane proteins [6,7].…”