Insights into substrate recognition and specificity for IgG by Endoglycosidase S2.

Antibodies bind foreign antigens with high affinity and specificity leading to their neutralization and/or clearance by the immune system. The conserved N-glycan on IgG has significant impact on antibody effector function, with the endoglycosidases of Streptococcus pyogenes deglycosylating the IgG t...

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Autores principales:	Asaminew H Aytenfisu, Daniel Deredge, Erik H Klontz, Jonathan Du, Eric J Sundberg, Alexander D MacKerell
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/1c5a1fb3a1a0497cac4852104caef0b6
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spelling	oai:doaj.org-article:1c5a1fb3a1a0497cac4852104caef0b62021-12-02T19:57:30ZInsights into substrate recognition and specificity for IgG by Endoglycosidase S2.1553-734X1553-735810.1371/journal.pcbi.1009103https://doaj.org/article/1c5a1fb3a1a0497cac4852104caef0b62021-07-01T00:00:00Zhttps://doi.org/10.1371/journal.pcbi.1009103https://doaj.org/toc/1553-734Xhttps://doaj.org/toc/1553-7358Antibodies bind foreign antigens with high affinity and specificity leading to their neutralization and/or clearance by the immune system. The conserved N-glycan on IgG has significant impact on antibody effector function, with the endoglycosidases of Streptococcus pyogenes deglycosylating the IgG to evade the immune system, a process catalyzed by the endoglycosidase EndoS2. Studies have shown that two of the four domains of EndoS2, the carbohydrate binding module (CBM) and the glycoside hydrolase (GH) domain are critical for catalytic activity. To yield structural insights into contributions of the CBM and the GH domains as well as the overall flexibility of EndoS2 to the proteins' catalytic activity, models of EndoS2-Fc complexes were generated through enhanced-sampling molecular-dynamics (MD) simulations and site-identification by ligand competitive saturation (SILCS) docking followed by reconstruction and multi-microsecond MD simulations. Modeling results predict that EndoS2 initially interacts with the IgG through its CBM followed by interactions with the GH yielding catalytically competent states. These may involve the CBM and GH of EndoS2 simultaneously interacting with either the same Fc CH2/CH3 domain or individually with the two Fc CH2/CH3 domains, with EndoS2 predicted to assume closed conformations in the former case and open conformations in the latter. Apo EndoS2 is predicted to sample both the open and closed states, suggesting that either complex can directly form following initial IgG-EndoS2 encounter. Interactions of the CBM and GH domains with the IgG are predicted to occur through both its glycan and protein regions. Simulations also predict that the Fc glycan can directly transfer from the CBM to the GH, facilitating formation of catalytically competent complexes and how the 734 to 751 loop on the CBM can facilitate extraction of the glycan away from the Fc CH2/CH3 domain. The predicted models are compared and consistent with Hydrogen/Deuterium Exchange data. In addition, the complex models are consistent with the high specificity of EndoS2 for the glycans on IgG supporting the validity of the predicted models.Asaminew H AytenfisuDaniel DeredgeErik H KlontzJonathan DuEric J SundbergAlexander D MacKerellPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Computational Biology, Vol 17, Iss 7, p e1009103 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Asaminew H Aytenfisu Daniel Deredge Erik H Klontz Jonathan Du Eric J Sundberg Alexander D MacKerell Insights into substrate recognition and specificity for IgG by Endoglycosidase S2.
description	Antibodies bind foreign antigens with high affinity and specificity leading to their neutralization and/or clearance by the immune system. The conserved N-glycan on IgG has significant impact on antibody effector function, with the endoglycosidases of Streptococcus pyogenes deglycosylating the IgG to evade the immune system, a process catalyzed by the endoglycosidase EndoS2. Studies have shown that two of the four domains of EndoS2, the carbohydrate binding module (CBM) and the glycoside hydrolase (GH) domain are critical for catalytic activity. To yield structural insights into contributions of the CBM and the GH domains as well as the overall flexibility of EndoS2 to the proteins' catalytic activity, models of EndoS2-Fc complexes were generated through enhanced-sampling molecular-dynamics (MD) simulations and site-identification by ligand competitive saturation (SILCS) docking followed by reconstruction and multi-microsecond MD simulations. Modeling results predict that EndoS2 initially interacts with the IgG through its CBM followed by interactions with the GH yielding catalytically competent states. These may involve the CBM and GH of EndoS2 simultaneously interacting with either the same Fc CH2/CH3 domain or individually with the two Fc CH2/CH3 domains, with EndoS2 predicted to assume closed conformations in the former case and open conformations in the latter. Apo EndoS2 is predicted to sample both the open and closed states, suggesting that either complex can directly form following initial IgG-EndoS2 encounter. Interactions of the CBM and GH domains with the IgG are predicted to occur through both its glycan and protein regions. Simulations also predict that the Fc glycan can directly transfer from the CBM to the GH, facilitating formation of catalytically competent complexes and how the 734 to 751 loop on the CBM can facilitate extraction of the glycan away from the Fc CH2/CH3 domain. The predicted models are compared and consistent with Hydrogen/Deuterium Exchange data. In addition, the complex models are consistent with the high specificity of EndoS2 for the glycans on IgG supporting the validity of the predicted models.
format	article
author	Asaminew H Aytenfisu Daniel Deredge Erik H Klontz Jonathan Du Eric J Sundberg Alexander D MacKerell
author_facet	Asaminew H Aytenfisu Daniel Deredge Erik H Klontz Jonathan Du Eric J Sundberg Alexander D MacKerell
author_sort	Asaminew H Aytenfisu
title	Insights into substrate recognition and specificity for IgG by Endoglycosidase S2.
title_short	Insights into substrate recognition and specificity for IgG by Endoglycosidase S2.
title_full	Insights into substrate recognition and specificity for IgG by Endoglycosidase S2.
title_fullStr	Insights into substrate recognition and specificity for IgG by Endoglycosidase S2.
title_full_unstemmed	Insights into substrate recognition and specificity for IgG by Endoglycosidase S2.
title_sort	insights into substrate recognition and specificity for igg by endoglycosidase s2.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/1c5a1fb3a1a0497cac4852104caef0b6
work_keys_str_mv	AT asaminewhaytenfisu insightsintosubstraterecognitionandspecificityforiggbyendoglycosidases2 AT danielderedge insightsintosubstraterecognitionandspecificityforiggbyendoglycosidases2 AT erikhklontz insightsintosubstraterecognitionandspecificityforiggbyendoglycosidases2 AT jonathandu insightsintosubstraterecognitionandspecificityforiggbyendoglycosidases2 AT ericjsundberg insightsintosubstraterecognitionandspecificityforiggbyendoglycosidases2 AT alexanderdmackerell insightsintosubstraterecognitionandspecificityforiggbyendoglycosidases2
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Insights into substrate recognition and specificity for IgG by Endoglycosidase S2.

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