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Mechanism of antibody-specific deglycosylation and immune evasion by Streptococcal IgG-specific endoglycosidases

Author

Listed:
  • Beatriz Trastoy

    (Biocruces Health Research Institute
    Basque Research and Technology Alliance (BRTA)
    Ikerbasque, Basque Foundation for Science)

  • Jonathan J. Du

    (Emory University School of Medicine)

  • Javier O. Cifuente

    (Biocruces Health Research Institute
    Basque Research and Technology Alliance (BRTA))

  • Lorena Rudolph

    (Institute of Chemistry and Metabolomics)

  • Mikel García-Alija

    (Biocruces Health Research Institute
    Basque Research and Technology Alliance (BRTA))

  • Erik H. Klontz

    (University of Maryland School of Medicine
    University of Maryland School of Medicine)

  • Daniel Deredge

    (University of Maryland School of Pharmacy)

  • Nazneen Sultana

    (Emory University School of Medicine)

  • Chau G. Huynh

    (Emory University School of Medicine)

  • Maria W. Flowers

    (Emory University School of Medicine)

  • Chao Li

    (University of Maryland)

  • Diego E. Sastre

    (Emory University School of Medicine)

  • Lai-Xi Wang

    (University of Maryland)

  • Francisco Corzana

    (Universidad de La Rioja)

  • Alvaro Mallagaray

    (Institute of Chemistry and Metabolomics)

  • Eric J. Sundberg

    (Emory University School of Medicine)

  • Marcelo E. Guerin

    (Biocruces Health Research Institute
    Basque Research and Technology Alliance (BRTA)
    Ikerbasque, Basque Foundation for Science)

Abstract

Bacterial pathogens have evolved intricate mechanisms to evade the human immune system, including the production of immunomodulatory enzymes. Streptococcus pyogenes serotypes secrete two multi-modular endo-β-N-acetylglucosaminidases, EndoS and EndoS2, that specifically deglycosylate the conserved N-glycan at Asn297 on IgG Fc, disabling antibody-mediated effector functions. Amongst thousands of known carbohydrate-active enzymes, EndoS and EndoS2 represent just a handful of enzymes that are specific to the protein portion of the glycoprotein substrate, not just the glycan component. Here, we present the cryoEM structure of EndoS in complex with the IgG1 Fc fragment. In combination with small-angle X-ray scattering, alanine scanning mutagenesis, hydrolytic activity measurements, enzyme kinetics, nuclear magnetic resonance and molecular dynamics analyses, we establish the mechanisms of recognition and specific deglycosylation of IgG antibodies by EndoS and EndoS2. Our results provide a rational basis from which to engineer novel enzymes with antibody and glycan selectivity for clinical and biotechnological applications.

Suggested Citation

  • Beatriz Trastoy & Jonathan J. Du & Javier O. Cifuente & Lorena Rudolph & Mikel García-Alija & Erik H. Klontz & Daniel Deredge & Nazneen Sultana & Chau G. Huynh & Maria W. Flowers & Chao Li & Diego E. , 2023. "Mechanism of antibody-specific deglycosylation and immune evasion by Streptococcal IgG-specific endoglycosidases," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37215-3
    DOI: 10.1038/s41467-023-37215-3
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    References listed on IDEAS

    as
    1. Mikel García-Alija & Jonathan J. Du & Izaskun Ordóñez & Asier Diz-Vallenilla & Alicia Moraleda-Montoya & Nazneen Sultana & Chau G. Huynh & Chao Li & Thomas Connor Donahue & Lai-Xi Wang & Beatriz Trast, 2022. "Mechanism of cooperative N-glycan processing by the multi-modular endoglycosidase EndoE," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    2. Beatriz Trastoy & Jonathan J. Du & Erik H. Klontz & Chao Li & Javier O. Cifuente & Lai-Xi Wang & Eric J. Sundberg & Marcelo E. Guerin, 2020. "Structural basis of mammalian high-mannose N-glycan processing by human gut Bacteroides," Nature Communications, Nature, vol. 11(1), pages 1-11, December.
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    Cited by:

    1. Diego E. Sastre & Nazneen Sultana & Marcos V. A. S. Navarro & Maros Huliciak & Jonathan Du & Javier O. Cifuente & Maria Flowers & Xu Liu & Pete Lollar & Beatriz Trastoy & Marcelo E. Guerin & Eric J. S, 2024. "Human gut microbes express functionally distinct endoglycosidases to metabolize the same N-glycan substrate," Nature Communications, Nature, vol. 15(1), pages 1-17, December.

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