2. Academic Validation
  3. N-linked glycosylation of SV2 is required for binding and uptake of botulinum neurotoxin A

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.
Guorui Yao 1,  Sicai Zhang 2 3 4,  Stefan Mahrhold 5,  Kwok-Ho Lam 1,  Daniel Stern 6,  Karine Bagramyan 7,  Kay Perry 8,  Markus Kalkum 7,  Andreas Rummel 5,  Min Dong 2 3 4,  Rongsheng Jin 1
Affiliations

Affiliations

  • 1 Department of Physiology and Biophysics, University of California, Irvine, Irvine, California, USA.
  • 2 Department of Urology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
  • 3 Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA.
  • 4 Department of Surgery, Harvard Medical School, Boston, Massachusetts, USA.
  • 5 Institut für Toxikologie, Medizinische Hochschule Hannover, Hannover, Germany.
  • 6 Centre for Biological Threats and Special Pathogens-Biological Toxins (ZBS3), Robert Koch-Institut, Berlin, Germany.
  • 7 Department of Molecular Immunology, Beckman Research Institute of City of Hope, Duarte, California, USA.
  • 8 NE-CAT, Argonne National Laboratory, Department of Chemistry and Chemical Biology, Cornell University, Argonne, Illinois, USA.
PMID: 27294781 DOI: 10.1038/nsmb.3245
Abstract

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.

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