Botulinum Neurotoxin A Selectively Cleaves the Synaptic Protein SNAP-25

Nature. 1993 Sep 9;365(6442):160-3. doi: 10.1038/365160a0.

Abstract

Neurotransmitter release is potently blocked by a group of structurally related toxin proteins produced by Clostridium botulinum. Botulinum neurotoxin type B (BoNT/B) and tetanus toxin (TeTx) are zinc-dependent proteases that specifically cleave synaptobrevin (VAMP), a membrane protein of synaptic vesicles. 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 catalytic 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Botulinum Toxins / pharmacology*
  • Glutamates / metabolism
  • Glutamic Acid
  • In Vitro Techniques
  • Membrane Proteins*
  • Nerve Tissue Proteins / metabolism*
  • Neurotransmitter Agents / metabolism
  • Synaptic Membranes / metabolism
  • Synaptosomal-Associated Protein 25
  • Synaptosomes / metabolism
  • Tetanus Toxin / pharmacology

Substances

  • Glutamates
  • Membrane Proteins
  • Nerve Tissue Proteins
  • Neurotransmitter Agents
  • Synaptosomal-Associated Protein 25
  • Tetanus Toxin
  • Glutamic Acid
  • Botulinum Toxins