Bespoke conformation and antibody recognition distinguishes the streptococcal immune evasion factors EndoS and EndoS2

Abstract

The IgG-specific endoglycosidases EndoS and EndoS2 from Streptococcus pyogenes ablate IgG function by removing the conserved N-linked glycans present on the Fc region. Their role in immune evasion, by inactivation of IgG antibodies, has led these enzymes to be investigated as therapeutics for suppressing unwanted immune activation. Their activity and precise substrate specificity has also prompted the development of these enzymes as tools for engineering IgG glycosylation. Recent structural studies have revealed how EndoS drives specificity for IgG by binding the Fc peptide surface with a domain that has homology for a carbohydrate-binding module (CBM). Here, we present the crystal structure of the EndoS2-IgG1 Fc complex at 3.0 [A] resolution. Comparison with the EndoS-IgG1 Fc structure reveals a similar mode of interaction, but slightly different orientations resulting from different interfaces with glycosidase and CBM domains, leading to recognition of distinct Fc surfaces. These findings rationalise previous observations that non-catalytic domains cannot readily be substituted. The structural information presented here will guide the continued development of IgG-specific endoglycosidases in antibody glycoengineering and immunotherapy.