6mdv
Crystal structure of Streptococcus pyogenes endo-beta-N-acetylglucosaminidase (EndoS2) with high-mannose glycanCrystal structure of Streptococcus pyogenes endo-beta-N-acetylglucosaminidase (EndoS2) with high-mannose glycan
Structural highlights
FunctionENDS2_STRP9 Endoglucosidase that acts as a host immune evasion factor by mediating hydrolysis of the N-linked glycan from the Fc region of host immunoglobulin-gamma (IgG) during infection (PubMed:23865566, PubMed:27288408, PubMed:26156869, PubMed:30937380). Specifically catalyzes the hydrolysis of the beta-1,4 linkage between the first two N-acetylglucosamine residues of the complex-type N-linked glycan located on 'Asn-297' of the Fc region of IgG antibodies (IGHG1, IGHG2, IGHG3 or IGHG4), thereby preventing interaction between IgGs and Fc receptors and ability to activate the complement pathway (By similarity). Also able to cleave biantennary and sialylated glycans of host alpha-1-acid glycoprotein (ORM1 or ORM2) (PubMed:23865566, PubMed:27288408). Acts on N-linked glycans with or without core fucosylation (PubMed:26156869, PubMed:27288408, PubMed:30937380). In contrast to EndoS, also able to process oligomannose- or hybrid-type glycans (PubMed:26156869, PubMed:30937380). Specifically acts on IgGs; does not act on immunoglobulin alpha, beta, delta or mu (PubMed:26156869).[UniProtKB:Q99Y92][1] [2] [3] [4] Publication Abstract from PubMedImmunoglobulin G (IgG) glycosylation critically modulates antibody effector functions. Streptococcus pyogenes secretes a unique endo-beta-N-acetylglucosaminidase, EndoS2, which deglycosylates the conserved N-linked glycan at Asn297 on IgG Fc to eliminate its effector functions and evade the immune system. EndoS2 and specific point mutants have been used to chemoenzymatically synthesize antibodies with customizable glycosylation for gain of functions. EndoS2 is useful in these schemes because it accommodates a broad range of N-glycans, including high-mannose, complex, and hybrid types; however, its mechanism of substrate recognition is poorly understood. We present crystal structures of EndoS2 alone and bound to complex and high-mannose glycans; the broad N-glycan specificity is governed by critical loops that shape the binding site of EndoS2. Furthermore, hydrolytic experiments, domain-swap chimeras, and hydrogen-deuterium exchange mass spectrometry reveal the importance of the carbohydrate-binding module in the mechanism of IgG recognition by EndoS2, providing insights into engineering enzymes to catalyze customizable glycosylation reactions. Molecular Basis of Broad Spectrum N-Glycan Specificity and Processing of Therapeutic IgG Monoclonal Antibodies by Endoglycosidase S2.,Klontz EH, Trastoy B, Deredge D, Fields JK, Li C, Orwenyo J, Marina A, Beadenkopf R, Gunther S, Flores J, Wintrode PL, Wang LX, Guerin ME, Sundberg EJ ACS Cent Sci. 2019 Mar 27;5(3):524-538. doi: 10.1021/acscentsci.8b00917. Epub, 2019 Feb 6. PMID:30937380[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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