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

  • Author(s): Yao, Guorui
  • Zhang, Sicai
  • Mahrhold, Stefan
  • Lam, Kwok-Ho
  • Stern, Daniel
  • Bagramyan, Karine
  • Perry, Kay
  • Kalkum, Markus
  • Rummel, Andreas
  • Dong, Min
  • Jin, Rongsheng
  • et al.

Published Web Location

https://doi.org/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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