Abstract
The clostridial neurotoxin family consists of tetanus neurotoxin and seven distinct botulinum neurotoxins which cause the diseases tetanus and botulism. The extreme potency of these toxins primarily relies not only on their ability to specifically enter motoneurons but also on the activity their catalytic domains display inside presynaptic motoneuronal terminals. Subsequent to neurotoxin binding and endocytosis the catalytic domains become translocated across endosomal membranes and proteolyze unique peptide bonds of one of three soluble N-ethylmaleimide-sensitive fusion protein attachment receptors (SNAREs), vesicle associated membrane protein/synaptobrevin, synaptosome associated protein of 25 kDa, or syntaxin. As these substrate proteins are core components of the vesicular membrane fusion apparatus, cleavage of any of the substrate molecules results in the blockade of neurotransmitter release. This review summarizes the present knowledge about the molecular basis of the specific substrate recognition and cleavage mechanism and assesses the feasibility of reengineering catalytic domains to hydrolyze non-substrate members of the three SNARE families in order to expand the therapeutic application of botulinum neurotoxins.
Highlights
Clostridial neurotoxins (CNT), a family of closely related bacterial protein toxins, consist of seven antigenically distinguishable botulinum neurotoxins (BoNTs) and tetanus neurotoxin (TeNT)
CNT is synthesized as a ~150 kDa single chain protein, but subsequently cleaved by specific clostridial or host proteases
C-terminal ~100 kDa heavy chain (HC). Both chains remain attached via a single disulfide bond formed between cysteines at the C-terminus of the light chain (LC) and the N-terminus of the HC, a peptide loop formed by the N-terminal ~55 amino acids of HC that wraps around the LC and further non-covalent interactions (Figure 1)
Summary
Clostridial neurotoxins (CNT), a family of closely related bacterial protein toxins, consist of seven antigenically distinguishable botulinum neurotoxins (BoNTs) and tetanus neurotoxin (TeNT). CNT is synthesized as a ~150 kDa single chain protein, but subsequently cleaved by specific clostridial or host proteases. CNTs reach cholinergic motor nerve terminals, where a four step process is initiated that renders a synapse inoperative. In order that they can be taken up via the recycling pathway of synaptic vesicles (SV), they first bind to complex gangliosides at the surface of nonmyelinated nerve terminals [1]. Whether in a cholinergic nerve terminal or in a neuron of the spinal cord, the toxins become exposed to an acidic environment during transport of the endocytosed vesicle which initiates the third step. BoNT/A and B have become widely used therapeutics for the treatment of a variety of neurological disorders with still increasing numbers of indications during the past two decades [18]
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