Structural basis of specific IgG deactivation by streptococcal immune evasion enzymes

Abstract

Enzymatic cleavage of IgG antibodies is a common strategy used by pathogens for the ablation of immune effector function. The bacterium Streptococcus pyogenes, for example, is a common human pathogen and is highly adapted for human infection. The bacterium secretes several enzymes which inactivate human IgG, including the protease IdeS and endoglycosidases EndoS/EndoS2, which catalyse cleavage and deglycosylation of IgG antibodies, respectively. This activity, along with their fine specificity for IgG, has enabled the development of these enzymes with diverse applications. IdeS has received clinical approval for use as a pre-treatment for hypersensitised patients undergoing kidney transplantation, and, along with EndoS, has been tested in several pre-clinical models of autoimmune disease. The endoglycosidases EndoS and EndoS2 have additional application in engineering antibody glycosylation. Despite these extensive therapeutic and biotechnological applications, the structural basis for how these enzymes specifically deactivate IgG is unclear.
This thesis presents crystal structures of IdeS, EndoS and EndoS2 in complex with their IgG1 Fc substrate, which were generated using “less-crystallisable” Fc variants, to evade the common bottleneck of preferential Fc self-crystallisation in the crystallisation of Fc-protein complexes. These structures reveal the molecular basis behind the exquisite specificity of each enzyme for IgG. The IdeS protease displays extensive Fc recognition and encases the antibody hinge region. Conversely, the glycan hydrolase domain in EndoS/EndoS2 traps the Fc glycan in a previously unobserved “flipped-out” conformation, while additional recognition of the Fc peptide surface is driven by the so-called carbohydrate-binding module. This work reveals the molecular basis of specific IgG deactivation by these streptococcal immune evasion enzymes, which will aid in the development of next-generation enzymes for a wide range of applications.

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Identifiers

ORCID for Abigail Sophie Louise Sudol: orcid.org/0000-0002-9420-9758

ORCID for Max Crispin: orcid.org/0000-0002-1072-2694

ORCID for Ivo Tews: orcid.org/0000-0002-4704-1139

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