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Botulinum neurotoxin A selectively cleaves the synaptic protein SNAP-25

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Abstract

NEUROTRANSMITTER release is potently blocked by a group of structurally related toxin proteins produced by Clostridium botulinum1. Botulinum neurotoxin type B (BoNT/B) and tetanus toxin (TeTx) are zinc-dependent proteases that specifically cleave synaptobrevin (VAMP), a membrane protein of synaptic vesicles2,3. Here we report that inhibition of transmitter release from synaptosomes caused by botulinum neurotoxin A (BoNT/A) is associated with the selective proteolysis of the synaptic protein SNAP-25. Furthermore, isolated or recombinant L chain of BoNT/A cleaves SNAP-25 in vitro. Cleavage occurred near the carboxyterminus and was sensitive to divalent cation chelators. In addition, a glutamate residue in the BoNT/A L chain, presumably required to stabilize a water molecule in the zinc-containing cata-lytic centre, was required for proteolytic activity. These findings demonstrate that BoNT/A acts as a zinc-dependent protease that selectively cleaves SNAP-25. Thus, a second component of the putative fusion complex mediating synaptic vesicle exocytosis is targeted by a clostridial neurotoxin.

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Authors and Affiliations

  1. Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut, 06510, USA

    Juan Blasi, Edwin R. Chapman, Egenhard Link & Reinhard Jahn

  2. Department ofCell Biology, and Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut, 06510, USA

    Pietro De Camilli & Reinhard Jahn

  3. Department of Cell Biology and Pathology, School of Medicine, University of Barcelona, Spain

    Juan Blasi

  4. Institute for Microbiology, Federal Research Centre for Virus Diseases of Animals, D-7400, Tubingen, Germany

    Thomas Binz, Shinji Yamasaki & Heiner Niemann

  5. Department of Molecular Genetics and Howard Hughes Medical Institute, Southwestern Medical Center, University of Texas, Dallas, Texas, 75235, USA

    Thomas C. Südhof

Authors
  1. Juan Blasi
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  2. Edwin R. Chapman
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  3. Thomas Binz
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  4. Shinji Yamasaki
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  5. Pietro De Camilli
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  6. Thomas C. Südhof
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  7. Heiner Niemann
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  8. Reinhard Jahn
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Blasi, J., Chapman, E., Link, E. et al. Botulinum neurotoxin A selectively cleaves the synaptic protein SNAP-25. Nature 365, 160–163 (1993). https://doi.org/10.1038/365160a0

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  • DOI: https://doi.org/10.1038/365160a0

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