Extensive substrate recognition by the streptococcal antibody-degrading enzymes IdeS and EndoS
Extensive substrate recognition by the streptococcal antibody-degrading enzymes IdeS and EndoS
Enzymatic cleavage of IgG antibodies is a common strategy used by pathogenic bacteria to ablate immune effector function. The Streptococcus pyogenes bacterium secretes the protease IdeS and the glycosidase EndoS, which specifically catalyse cleavage and deglycosylation of human IgG, respectively. IdeS has received clinical approval for kidney transplantation in hypersensitised individuals, while EndoS has found application in engineering antibody glycosylation. We present crystal structures of both enzymes in complex with their IgG1 Fc substrate, which was achieved using Fc engineering to disfavour preferential Fc crystallisation. The IdeS protease displays extensive Fc recognition and encases the antibody hinge. Conversely, the glycan hydrolase domain in EndoS traps the Fc glycan in a "flipped-out" conformation, while additional recognition of the Fc peptide is driven by the so-called carbohydrate binding module. In this work, we reveal the molecular basis of antibody recognition by bacterial enzymes, providing a template for the development of next-generation enzymes.
Sudol, Abigail S L
edd31bca-5f7f-4c17-9f50-b76cadb3a311
Butler, John
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Ivory, Dylan P
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Tews, Ivo
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Crispin, Max
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17 December 2022
Sudol, Abigail S L
edd31bca-5f7f-4c17-9f50-b76cadb3a311
Butler, John
5132f0e2-f28d-412a-be9a-e97963b4c0ee
Ivory, Dylan P
e8a77800-8dc7-4272-ab28-060de46bb278
Tews, Ivo
9117fc5e-d01c-4f8d-a734-5b14d3eee8dd
Crispin, Max
cd980957-0943-4b89-b2b2-710f01f33bc9
Sudol, Abigail S L, Butler, John, Ivory, Dylan P, Tews, Ivo and Crispin, Max
(2022)
Extensive substrate recognition by the streptococcal antibody-degrading enzymes IdeS and EndoS.
Nature Communications, 13 (1), [7801].
(doi:10.1038/s41467-022-35340-z).
Abstract
Enzymatic cleavage of IgG antibodies is a common strategy used by pathogenic bacteria to ablate immune effector function. The Streptococcus pyogenes bacterium secretes the protease IdeS and the glycosidase EndoS, which specifically catalyse cleavage and deglycosylation of human IgG, respectively. IdeS has received clinical approval for kidney transplantation in hypersensitised individuals, while EndoS has found application in engineering antibody glycosylation. We present crystal structures of both enzymes in complex with their IgG1 Fc substrate, which was achieved using Fc engineering to disfavour preferential Fc crystallisation. The IdeS protease displays extensive Fc recognition and encases the antibody hinge. Conversely, the glycan hydrolase domain in EndoS traps the Fc glycan in a "flipped-out" conformation, while additional recognition of the Fc peptide is driven by the so-called carbohydrate binding module. In this work, we reveal the molecular basis of antibody recognition by bacterial enzymes, providing a template for the development of next-generation enzymes.
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s41467-022-35340-z
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Accepted/In Press date: 25 November 2022
Published date: 17 December 2022
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Funding Information:
We are grateful to the beamline scientists on I03 at Diamond Light Source (DLS) and ID30A-3 at the European Synchrotron Radiation Facility (ESRF), and to Chris Holes for his support with the macromolecular crystallisation facility at the University of Southampton. This work was supported by DLS, ESRF (MX2373) and the School of Biological Sciences, University of Southampton.
Funding Information:
We are grateful to the beamline scientists on I03 at Diamond Light Source (DLS) and ID30A-3 at the European Synchrotron Radiation Facility (ESRF), and to Chris Holes for his support with the macromolecular crystallisation facility at the University of Southampton. This work was supported by DLS, ESRF (MX2373) and the School of Biological Sciences, University of Southampton.
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© 2022, The Author(s).
Identifiers
Local EPrints ID: 473784
URI: http://eprints.soton.ac.uk/id/eprint/473784
ISSN: 2041-1723
PURE UUID: 50e7f9ab-49a4-4ba4-a749-425bd77ebee6
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Date deposited: 31 Jan 2023 17:50
Last modified: 27 Mar 2024 02:56
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Dylan P Ivory
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