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

  • Author(s): Yao, G
  • Zhang, S
  • Mahrhold, S
  • Lam, KH
  • Stern, D
  • Bagramyan, K
  • Perry, K
  • Kalkum, M
  • Rummel, A
  • Dong, M
  • Jin, R
  • et al.

Published Web Location

https://doi.org/10.1038/nsmb.3245
Abstract

© 2016 Nature America, Inc. All rights reserved. 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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