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N-linked glycosylation of SV2 is required for binding and uptake of botulinum neurotoxin A.
Yao, Guorui; Zhang, Sicai; Mahrhold, Stefan; Lam, Kwok-Ho; Stern, Daniel; Bagramyan, Karine; Perry, Kay; Kalkum, Markus; Rummel, Andreas; Dong, Min; Jin, Rongsheng.
Afiliación
  • Yao G; Department of Physiology and Biophysics, University of California, Irvine, Irvine, California, USA.
  • Zhang S; Department of Urology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
  • Mahrhold S; Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA.
  • Lam KH; Department of Surgery, Harvard Medical School, Boston, Massachusetts, USA.
  • Stern D; Institut für Toxikologie, Medizinische Hochschule Hannover, Hannover, Germany.
  • Bagramyan K; Department of Physiology and Biophysics, University of California, Irvine, Irvine, California, USA.
  • Perry K; Centre for Biological Threats and Special Pathogens-Biological Toxins (ZBS3), Robert Koch-Institut, Berlin, Germany.
  • Kalkum M; Department of Molecular Immunology, Beckman Research Institute of City of Hope, Duarte, California, USA.
  • Rummel A; NE-CAT, Argonne National Laboratory, Department of Chemistry and Chemical Biology, Cornell University, Argonne, Illinois, USA.
  • Dong M; Department of Molecular Immunology, Beckman Research Institute of City of Hope, Duarte, California, USA.
  • Jin R; Institut für Toxikologie, Medizinische Hochschule Hannover, Hannover, Germany.
Nat Struct Mol Biol ; 23(7): 656-62, 2016 07.
Article en En | MEDLINE | ID: mdl-27294781
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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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Glicoproteínas de Membrana / Procesamiento Proteico-Postraduccional / Clostridium botulinum / Toxinas Botulínicas Tipo A / Anticuerpos Monoclonales / Antídotos / Proteínas del Tejido Nervioso Límite: Humans Idioma: En Revista: Nat Struct Mol Biol Asunto de la revista: BIOLOGIA MOLECULAR Año: 2016 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Glicoproteínas de Membrana / Procesamiento Proteico-Postraduccional / Clostridium botulinum / Toxinas Botulínicas Tipo A / Anticuerpos Monoclonales / Antídotos / Proteínas del Tejido Nervioso Límite: Humans Idioma: En Revista: Nat Struct Mol Biol Asunto de la revista: BIOLOGIA MOLECULAR Año: 2016 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos