2. Academic Validation
  3. Mechanism of antibody-specific deglycosylation and immune evasion by Streptococcal IgG-specific endoglycosidases

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

  • Nat Commun. 2023 Mar 27;14(1):1705. doi: 10.1038/s41467-023-37215-3.
Beatriz Trastoy # 1 2 3,  Jonathan J Du # 4,  Javier O Cifuente # 5 6,  Lorena Rudolph 7,  Mikel García-Alija 5 6,  Erik H Klontz 8 9,  Daniel Deredge 10,  Nazneen Sultana 4,  Chau G Huynh 4,  Maria W Flowers 4,  Chao Li 11,  Diego E Sastre 4,  Lai-Xi Wang 11,  Francisco Corzana 12,  Alvaro Mallagaray 13,  Eric J Sundberg 14,  Marcelo E Guerin 15 16 17
Affiliations

Affiliations

  • 1 Structural Glycobiology Laboratory, Biocruces Health Research Institute, Barakaldo, Bizkaia, 48903, Spain. beatriz.trastoy@gmail.com.
  • 2 Structural Glycobiology Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 801A, 48160, Derio, Spain. beatriz.trastoy@gmail.com.
  • 3 Ikerbasque, Basque Foundation for Science, 48009, Bilbao, Spain. beatriz.trastoy@gmail.com.
  • 4 Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, 30322, USA.
  • 5 Structural Glycobiology Laboratory, Biocruces Health Research Institute, Barakaldo, Bizkaia, 48903, Spain.
  • 6 Structural Glycobiology Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 801A, 48160, Derio, Spain.
  • 7 University of Lübeck, Center of Structural and Cell Biology in Medicine (CSCM), Institute of Chemistry and Metabolomics, Ratzeburger Allee 160, 23562, Lübeck, Germany.
  • 8 Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.
  • 9 Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.
  • 10 Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD, 21201, USA.
  • 11 Department of Chemistry and Biochemistry, University of Maryland, College Park, MD, 20742, USA.
  • 12 Departamento Química and Centro de Investigación en Síntesis Quı́mica, Universidad de La Rioja, 26006, Rioja, Spain.
  • 13 University of Lübeck, Center of Structural and Cell Biology in Medicine (CSCM), Institute of Chemistry and Metabolomics, Ratzeburger Allee 160, 23562, Lübeck, Germany. alvaro.mallagaraydebenito@uni-luebeck.de.
  • 14 Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, 30322, USA. eric.sundberg@emory.edu.
  • 15 Structural Glycobiology Laboratory, Biocruces Health Research Institute, Barakaldo, Bizkaia, 48903, Spain. mrcguerin@gmail.com.
  • 16 Structural Glycobiology Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 801A, 48160, Derio, Spain. mrcguerin@gmail.com.
  • 17 Ikerbasque, Basque Foundation for Science, 48009, Bilbao, Spain. mrcguerin@gmail.com.
  • # Contributed equally.
PMID: 36973249 DOI: 10.1038/s41467-023-37215-3
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.

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