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

Author:

Trastoy BeatrizORCID,Du Jonathan J.,Cifuente Javier O.ORCID,Rudolph LorenaORCID,García-Alija Mikel,Klontz Erik H.,Deredge DanielORCID,Sultana NazneenORCID,Huynh Chau G.,Flowers Maria W.,Li Chao,Sastre Diego E.,Wang Lai-XiORCID,Corzana FranciscoORCID,Mallagaray AlvaroORCID,Sundberg Eric J.ORCID,Guerin Marcelo E.ORCID

Abstract

AbstractBacterial 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.

Funder

Ministry of Economy and Competitiveness | Agencia Estatal de Investigación

Eusko Jaurlaritza

U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary

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