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Molecular Basis of Broad Spectrum N-Glycan Specificity and Processing of Therapeutic IgG Monoclonal Antibodies by Endoglycosidase S2.

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Klontz EH, Trastoy B, Deredge D, Fields JK, Li C, Orwenyo J, Marina A, Beadenkopf R, Günther S, Flores J, Wintrode PL, Wang LX, Guerin ME, Sundberg EJ
OpenAccess logo ACS Cent Sci 5 524-538 (2019)
Related entries: 6e58, 6mds

Cited: 17 times
EuropePMC logo PMID: 30937380

Abstract

Immunoglobulin G (IgG) glycosylation critically modulates antibody effector functions. Streptococcus pyogenes secretes a unique endo-β-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.

Reviews - 6mdv mentioned but not cited (1)

  1. Sculpting therapeutic monoclonal antibody N-glycans using endoglycosidases. Trastoy B, Du JJ, García-Alija M, Li C, Klontz EH, Wang LX, Sundberg EJ, Guerin ME. Curr Opin Struct Biol 72 248-259 (2022)

Articles - 6mdv mentioned but not cited (5)

  1. Structural basis of mammalian high-mannose N-glycan processing by human gut Bacteroides. Trastoy B, Du JJ, Klontz EH, Li C, Cifuente JO, Wang LX, Sundberg EJ, Guerin ME. Nat Commun 11 899 (2020)
  2. Structural basis for the specific cleavage of core-fucosylated N-glycans by endo-β-N-acetylglucosaminidase from the fungus Cordyceps militaris. Seki H, Huang Y, Arakawa T, Yamada C, Kinoshita T, Iwamoto S, Higuchi Y, Takegawa K, Fushinobu S. J Biol Chem 294 17143-17154 (2019)
  3. GH18 endo-β-N-acetylglucosaminidases use distinct mechanisms to process hybrid-type N-linked glycans. Trastoy B, Du JJ, Li C, García-Alija M, Klontz EH, Roberts BR, Donahue TC, Wang LX, Sundberg EJ, Guerin ME. J Biol Chem 297 101011 (2021)
  4. Mechanism of cooperative N-glycan processing by the multi-modular endoglycosidase EndoE. García-Alija M, Du JJ, Ordóñez I, Diz-Vallenilla A, Moraleda-Montoya A, Sultana N, Huynh CG, Li C, Donahue TC, Wang LX, Trastoy B, Sundberg EJ, Guerin ME. Nat Commun 13 1137 (2022)
  5. Insights into substrate recognition and specificity for IgG by Endoglycosidase S2. Aytenfisu AH, Deredge D, Klontz EH, Du J, Sundberg EJ, MacKerell AD. PLoS Comput Biol 17 e1009103 (2021)


Reviews citing this publication (4)

  1. Advances in Hydrogen/Deuterium Exchange Mass Spectrometry and the Pursuit of Challenging Biological Systems. James EI, Murphree TA, Vorauer C, Engen JR, Guttman M. Chem Rev 122 7562-7623 (2022)
  2. On enzymatic remodeling of IgG glycosylation; unique tools with broad applications. Sjögren J, Lood R, Nägeli A. Glycobiology 30 254-267 (2020)
  3. Structural insights into the mechanisms and specificities of IgG-active endoglycosidases. Du JJ, Klontz EH, Guerin ME, Trastoy B, Sundberg EJ. Glycobiology 30 268-279 (2020)
  4. Potential Applications of Endo-β-N-Acetylglucosaminidases From Bifidobacterium longum Subspecies infantis in Designing Value-Added, Next-Generation Infant Formulas. Duman H, Kaplan M, Arslan A, Sahutoglu AS, Kayili HM, Frese SA, Karav S. Front Nutr 8 646275 (2021)

Articles citing this publication (7)

  1. Characterization of the β-glucuronidase Pn3Pase as the founding member of glycoside hydrolase family GH169. Wantuch PL, Jella S, Duke JA, Mousa JJ, Henrissat B, Glushka J, Avci FY. Glycobiology 31 266-274 (2021)
  2. Structural insights of two novel N-acetyl-glucosaminidase enzymes through in silico methods. ŞahutoĞlu AS, Duman H, Frese SA, Karav S. Turk J Chem 44 1703-1712 (2020)
  3. Extensive substrate recognition by the streptococcal antibody-degrading enzymes IdeS and EndoS. Sudol ASL, Butler J, Ivory DP, Tews I, Crispin M. Nat Commun 13 7801 (2022)
  4. Endoglycosidase assay using enzymatically synthesized fluorophore-labeled glycans as substrates to uncover enzyme substrate specificities. Wu ZL, Ertelt JM. Commun Biol 5 501 (2022)
  5. Mass Spectrometry-Based Methods to Determine the Substrate Specificities and Kinetics of N-Linked Glycan Hydrolysis by Endo-β-N-Acetylglucosaminidases. Du JJ, Sastre D, Trastoy B, Roberts B, Deredge D, Klontz EH, Flowers MW, Sultana N, Guerin ME, Sundberg EJ. Methods Mol Biol 2674 147-167 (2023)
  6. Mechanism of antibody-specific deglycosylation and immune evasion by Streptococcal IgG-specific endoglycosidases. Trastoy B, Du JJ, Cifuente JO, Rudolph L, García-Alija M, Klontz EH, Deredge D, Sultana N, Huynh CG, Flowers MW, Li C, Sastre DE, Wang LX, Corzana F, Mallagaray A, Sundberg EJ, Guerin ME. Nat Commun 14 1705 (2023)
  7. Turning universal O into rare Bombay type blood. Anso I, Naegeli A, Cifuente JO, Orrantia A, Andersson E, Zenarruzabeitia O, Moraleda-Montoya A, García-Alija M, Corzana F, Del Orbe RA, Borrego F, Trastoy B, Sjögren J, Guerin ME. Nat Commun 14 1765 (2023)


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