The mechanistic basis for interprotomer deglycosylation of antibodies by corynebacterial IgG-specific endoglycosidases

Corynebacterium diphtheriae clade species secrete single-domain endo-β-N-acetylglucosaminidases (ENGases) that specifically bind to human IgG antibodies and hydrolyze their N297-linked glycans. Here, we define the molecular mechanisms of IgG-specific deglycosylation for the entire family of coryneba...

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Detalles Bibliográficos
Autores: Sastre, Diego E., Bournazos, Stylianos, Huliciak, Maros, Grace, Barbara Ann C., Boder, E. Josephine, Du, Jonathan, Sultana, Nazneen, Azzam, Tala, Brown, Trenton J., Flowers, Maria W., Lollar, Pete, Xu, Ting, Chernova, Tatiana A., Keith, Alasdair D., Keen, Meredith, Saltzman, Abigail, Martinez Gascueña, Ana, Trastoy, Beatriz, Guerin, Marcelo E., Frank, Filipp, Ortlund, Eric A., Ravetch, Jeffrey V., Sundberg, Eric J.
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2025
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/421158
Acceso en línea:http://hdl.handle.net/10261/421158
https://api.elsevier.com/content/abstract/scopus_id/105010127229
Access Level:acceso abierto
Palabra clave:Glycobiology
Glycosylation
Immune evasion
Microbiology
Structural biology
Descripción
Sumario:Corynebacterium diphtheriae clade species secrete single-domain endo-β-N-acetylglucosaminidases (ENGases) that specifically bind to human IgG antibodies and hydrolyze their N297-linked glycans. Here, we define the molecular mechanisms of IgG-specific deglycosylation for the entire family of corynebacterial IgG-specific ENGases, including but not limited to CU43 and CM49. By solving the crystal structure of CU43 in a 1:1 complex with the IgG1 Fc region, combined with targeted and saturation mutagenesis analysis and activity measurements using engineered antibodies, we establish an inter-protomeric mechanism of recognition and deglycosylation of IgG antibodies. Using in silico modeling, small-angle X-ray scattering and saturation mutagenesis we determine that CM49 uses a unique binding site on the Fc region, to process N297-linked glycans. Moreover, we demonstrate that CU43 treatment is highly effective in abrogating Fc effector functions in humanized mouse models, while preserving the neutralizing capacity of anti-influenza IgG antibodies, thereby conferring protection against lethal influenza challenge.

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