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Clostridial Neurotoxins: Mechanism of SNARE Cleavage and Outlook on Potential Substrate Specificity Reengineering
Institut für Biochemie, OE 4310, Medizinische Hochschule Hannover, 30623 Hannover, Germany
* Author to whom correspondence should be addressed.
Received: 7 February 2010; in revised form: 30 March 2010 / Accepted: 9 April 2010 / Published: 13 April 2010
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.
Keywords: botulinum neurotoxin; tetanus toxin; SNARE; zinc protease; enzyme engineering
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Binz, T.; Sikorra, S.; Mahrhold, S. Clostridial Neurotoxins: Mechanism of SNARE Cleavage and Outlook on Potential Substrate Specificity Reengineering. Toxins 2010, 2, 665-682.
Binz T, Sikorra S, Mahrhold S. Clostridial Neurotoxins: Mechanism of SNARE Cleavage and Outlook on Potential Substrate Specificity Reengineering. Toxins. 2010; 2(4):665-682.
Binz, Thomas; Sikorra, Stefan; Mahrhold, Stefan. 2010. "Clostridial Neurotoxins: Mechanism of SNARE Cleavage and Outlook on Potential Substrate Specificity Reengineering." Toxins 2, no. 4: 665-682.