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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.
Bacterial pathogens have evolved intricate mechanisms to evade the human immune system, including the production of immunomodulatory enzymes. Here, the authors establish the mechanisms of recognition and specific deglycosylation of IgG antibodies by the multi-modular enzymes EndoS and EndoS2
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1 Biocruces Health Research Institute, Structural Glycobiology Laboratory, Barakaldo, Spain (GRID:grid.452310.1); Basque Research and Technology Alliance (BRTA), Structural Glycobiology Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE), Derio, Spain (GRID:grid.420175.5) (ISNI:0000 0004 0639 2420); Ikerbasque, Basque Foundation for Science, Bilbao, Spain (GRID:grid.424810.b) (ISNI:0000 0004 0467 2314)
2 Emory University School of Medicine, Department of Biochemistry, Atlanta, USA (GRID:grid.189967.8) (ISNI:0000 0001 0941 6502)
3 Biocruces Health Research Institute, Structural Glycobiology Laboratory, Barakaldo, Spain (GRID:grid.452310.1); Basque Research and Technology Alliance (BRTA), Structural Glycobiology Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE), Derio, Spain (GRID:grid.420175.5) (ISNI:0000 0004 0639 2420)
4 Institute of Chemistry and Metabolomics, University of Lübeck, Center of Structural and Cell Biology in Medicine (CSCM), Lübeck, Germany (GRID:grid.4562.5) (ISNI:0000 0001 0057 2672)
5 University of Maryland School of Medicine, Department of Microbiology and Immunology, Baltimore, USA (GRID:grid.411024.2) (ISNI:0000 0001 2175 4264); University of Maryland School of Medicine, Institute of Human Virology, Baltimore, USA (GRID:grid.411024.2) (ISNI:0000 0001 2175 4264)
6 University of Maryland School of Pharmacy, Department of Pharmaceutical Sciences, Baltimore, USA (GRID:grid.411024.2) (ISNI:0000 0001 2175 4264)
7 University of Maryland, Department of Chemistry and Biochemistry, College Park, USA (GRID:grid.164295.d) (ISNI:0000 0001 0941 7177)
8 Universidad de La Rioja, Departamento Química and Centro de Investigación en Síntesis Quı́mica, Rioja, Spain (GRID:grid.119021.a) (ISNI:0000 0001 2174 6969)