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Protease Activity of the Botulinum Neurotoxins

  • Sheng Chen
  • Joseph T. Barbieri
Chapter
Part of the Current Topics in Neurotoxicity book series (Current Topics Neurotoxicity, volume 4)

Abstract

The flaccid pathology associated with intoxication by the botulinum neurotoxins (BoNTs) is the result of the association of the toxin to neuronal-specific host receptors and the cleavage of neuronal substrates, soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins. Each of the seven serotypes of BoNTs (A–G) targets a specific neuronal SNARE protein(s) for cleavage. Neuronal SNARE proteins function in the binding and fusion of neurotransmitter vesicles with a host membrane, and SNARE protein cleavage by the BoNTs disrupts the fusion process leading to host paralysis. The mechanism that BoNTs utilize to bind and cleave the SNARE proteins involves recognizing an extended substrate surface to allow the BoNTs to efficiently cleave the coiled SNARE protein substrate. BoNT serotypes comprise natural variants termed subtypes, which extends the complexity and potential pathology of the BoNTs. Understanding the mechanisms of BoNT action provides tools towards the development of strategies to identify novel small-molecule inhibitors of BoNT catalysis and to extend the use of BoNTs as therapeutic agents.

Keywords

Botulinum neurotoxin SNARE proteins v-SNARE t-SNARE Zinc-metalloprotease Syntaxin Synaptosomal-associated protein of 25 kDa (SNAP-25) Synaptobrevin Vesicle associated membrane protein (VAMP) Exosites Scissile bond “Pocket” model Belt region 

Notes

Acknowledgments

JTB acknowledges membership in the GLRCE and support by 1-U54-AI-057153 from Region V Great Lakes Regional Center of Excellence, the National Institute of Allergy and Infectious Diseases (NIAID), and National Institutes of Health Regional Center of Excellence for Bio-defense and Emerging Infectious Diseases Research Program and NIH-AI-030162. Sheng Chen is funded from the Research Grants Council (RGC)/PolyU Competitive Research Grants: G-U662, A-PK05, and G-YJ15.

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Copyright information

© Springer New York 2014

Authors and Affiliations

  1. 1.The Hong Kong Polytechnic UniversityHung HomHong Kong
  2. 2.Microbiology and Molecular GeneticsMedical College of WisconsinMilwaukeeUSA

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