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<p><i>Corynebacterium diphtheriae</i> clade species secrete single-domain endo-β-<i>N</i>-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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月4日

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  • Diego E. Sastre,
  • Stylianos Bournazos,
  • Maros Huliciak,
  • Barbara Ann C. Grace,
  • E. Josephine Boder,
  • Jonathan Du,
  • Nazneen Sultana,
  • Tala Azzam,
  • Trenton J. Brown,
  • Maria W. Flowers,
  • Pete Lollar,
  • Ting Xu,
  • Tatiana A. Chernova,
  • Alasdair D. Keith,
  • Meredith Keen,
  • Abigail Saltzman,
  • Ana Martinez Gascueña,
  • Beatriz Trastoy,
  • Marcelo E. Guerin,
  • Filipp Frank,
  • Eric A. Ortlund,
  • Jeffrey V. Ravetch,
  • Eric J. Sundberg

摘要

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.