Crystal structure of Streptococcus pyogenes EndoS, an immunomodulatory endoglycosidase specific for human IgG antibodies
Authors
Trastoy, BeatrizLomino, Joseph V.
Pierce, Brian G.
Carter, Lester G.
Gunther, Sebastian
Giddens, John P.
Snyder, Greg A.
Weiss, Thomas M.
Weng, Zhiping
Wang, Lai-Xi
Sundberg, Eric J.
UMass Chan Affiliations
Department of Biochemistry and Molecular PharmacologyProgram in Bioinformatics and Integrative Biology
Document Type
Journal ArticlePublication Date
2014-05-06Keywords
Bacterial ProteinsCatalytic Domain
Crystallography, X-Ray
Glycoside Hydrolases
Humans
Immunoglobulin Fc Fragments
Immunoglobulin G
Immunologic Factors
Models, Molecular
Protein Conformation
Protein Structure, Tertiary
Scattering, Small Angle
Streptococcus pyogenes
Substrate Specificity
X-Ray Diffraction
Biochemistry, Biophysics, and Structural Biology
Bioinformatics
Computational Biology
Integrative Biology
Systems Biology
Metadata
Show full item recordAbstract
To evade host immune mechanisms, many bacteria secrete immunomodulatory enzymes. Streptococcus pyogenes, one of the most common human pathogens, secretes a large endoglycosidase, EndoS, which removes carbohydrates in a highly specific manner from IgG antibodies. This modification renders antibodies incapable of eliciting host effector functions through either complement or Fc gamma receptors, providing the bacteria with a survival advantage. On account of this antibody-specific modifying activity, EndoS is being developed as a promising injectable therapeutic for autoimmune diseases that rely on autoantibodies. Additionally, EndoS is a key enzyme used in the chemoenzymatic synthesis of homogenously glycosylated antibodies with tailored Fc gamma receptor-mediated effector functions. Despite the tremendous utility of this enzyme, the molecular basis of EndoS specificity for, and processing of, IgG antibodies has remained poorly understood. Here, we report the X-ray crystal structure of EndoS and provide a model of its encounter complex with its substrate, the IgG1 Fc domain. We show that EndoS is composed of five distinct protein domains, including glycosidase, leucine-rich repeat, hybrid Ig, carbohydrate binding module, and three-helix bundle domains, arranged in a distinctive V-shaped conformation. Our data suggest that the substrate enters the concave interior of the enzyme structure, is held in place by the carbohydrate binding module, and that concerted conformational changes in both enzyme and substrate are required for subsequent antibody deglycosylation. The EndoS structure presented here provides a framework from which novel endoglycosidases could be engineered for additional clinical and biotechnological applications.Source
Proc Natl Acad Sci U S A. 2014 May 6;111(18):6714-9. doi: 10.1073/pnas.1322908111. Epub 2014 Apr 21. Link to article on publisher's siteDOI
10.1073/pnas.1322908111Permanent Link to this Item
http://hdl.handle.net/20.500.14038/25913PubMed ID
24753590Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1073/pnas.1322908111