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

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

Author information

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.

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.

PMID:
27294781
PMCID:
PMC5033645
DOI:
10.1038/nsmb.3245
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

The authors declare no competing financial interests.

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