N-linked glycosylation of SV2 is required for binding and uptake of botulinum neurotoxin A

Nat Struct Mol Biol. 2016 Jul;23(7):656-62. doi: 10.1038/nsmb.3245. Epub 2016 Jun 13.


Botulinum neurotoxin serotype A1 (BoNT/A1), a licensed drug widely used for medical and cosmetic applications, exerts its action by invading motoneurons. Here we report a 2.0-Å-resolution crystal structure of the BoNT/A1 receptor-binding domain in complex with its neuronal receptor, glycosylated human SV2C. We found that the neuronal tropism of BoNT/A1 requires recognition of both the peptide moiety and an N-linked glycan on SV2. This N-glycan-which is conserved in all SV2 isoforms across vertebrates-is essential for BoNT/A1 binding to neurons and for its potent neurotoxicity. The glycan-binding interface on SV2 is targeted by a human BoNT/A1-neutralizing antibody currently licensed as an antibotulism drug. Our studies reveal a new paradigm of host-pathogen interactions, in which pathogens exploit conserved host post-translational modifications, thereby achieving highly specific receptor binding while also tolerating genetic changes across multiple isoforms of receptors.

MeSH terms

  • Amino Acid Sequence
  • Antibodies, Monoclonal / chemistry*
  • Antidotes / chemistry*
  • Binding Sites
  • Biological Transport
  • Botulinum Toxins, Type A / chemistry*
  • Botulinum Toxins, Type A / metabolism
  • Cloning, Molecular
  • Clostridium botulinum / chemistry*
  • Clostridium botulinum / pathogenicity
  • Crystallography, X-Ray
  • Escherichia coli / genetics
  • Escherichia coli / metabolism
  • Gene Expression
  • Glycosylation
  • HEK293 Cells
  • Humans
  • Membrane Glycoproteins / antagonists & inhibitors
  • Membrane Glycoproteins / chemistry
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism*
  • Models, Molecular
  • Nerve Tissue Proteins / antagonists & inhibitors
  • Nerve Tissue Proteins / chemistry
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Protein Binding
  • Protein Domains
  • Protein Processing, Post-Translational*
  • Protein Structure, Secondary
  • Recombinant Fusion Proteins / chemistry
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism


  • Antibodies, Monoclonal
  • Antidotes
  • Membrane Glycoproteins
  • Nerve Tissue Proteins
  • Recombinant Fusion Proteins
  • SV2C protein, human
  • Botulinum Toxins, Type A