Structural basis for recognition of synaptic vesicle protein 2C by botulinum neurotoxin A

Nature. 2014 Jan 2;505(7481):108-11. doi: 10.1038/nature12732. Epub 2013 Nov 17.


Botulinum neurotoxin A (BoNT/A) belongs to the most dangerous class of bioweapons. Despite this, BoNT/A is used to treat a wide range of common medical conditions such as migraines and a variety of ocular motility and movement disorders. BoNT/A is probably best known for its use as an antiwrinkle agent in cosmetic applications (including Botox and Dysport). BoNT/A application causes long-lasting flaccid paralysis of muscles through inhibiting the release of the neurotransmitter acetylcholine by cleaving synaptosomal-associated protein 25 (SNAP-25) within presynaptic nerve terminals. Two types of BoNT/A receptor have been identified, both of which are required for BoNT/A toxicity and are therefore likely to cooperate with each other: gangliosides and members of the synaptic vesicle glycoprotein 2 (SV2) family, which are putative transporter proteins that are predicted to have 12 transmembrane domains, associate with the receptor-binding domain of the toxin. Recently, fibroblast growth factor receptor 3 (FGFR3) has also been reported to be a potential BoNT/A receptor. In SV2 proteins, the BoNT/A-binding site has been mapped to the luminal domain, but the molecular details of the interaction between BoNT/A and SV2 are unknown. Here we determined the high-resolution crystal structure of the BoNT/A receptor-binding domain (BoNT/A-RBD) in complex with the SV2C luminal domain (SV2C-LD). SV2C-LD consists of a right-handed, quadrilateral β-helix that associates with BoNT/A-RBD mainly through backbone-to-backbone interactions at open β-strand edges, in a manner that resembles the inter-strand interactions in amyloid structures. Competition experiments identified a peptide that inhibits the formation of the complex. Our findings provide a strong platform for the development of novel antitoxin agents and for the rational design of BoNT/A variants with improved therapeutic properties.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Botulinum Toxins, Type A / chemistry*
  • Botulinum Toxins, Type A / metabolism*
  • Crystallography, X-Ray
  • Endocytosis / drug effects
  • HEK293 Cells
  • Humans
  • Membrane Glycoproteins / chemistry*
  • Membrane Glycoproteins / metabolism*
  • Models, Molecular
  • Neostriatum / cytology
  • Nerve Tissue Proteins / chemistry*
  • Nerve Tissue Proteins / metabolism*
  • Neurons / drug effects
  • Peptide Fragments / chemistry
  • Peptide Fragments / pharmacology
  • Structure-Activity Relationship


  • Membrane Glycoproteins
  • Nerve Tissue Proteins
  • Peptide Fragments
  • SV2C protein, human
  • Botulinum Toxins, Type A

Associated data

  • PDB/4JRA