The mechanistic basis for interprotomer deglycosylation of antibodies by corynebacterial IgG-specific endoglycosidases

Diego E. Sastre (), Stylianos Bournazos, Maros Huliciak, Barbara Ann C. Grace, E. Josephine Boder, Jonathan Du, Nazneen Sultana, Tala Azzam, Trenton J. Brown, Maria W. Flowers, Pete Lollar, Ting Xu, Tatiana A. Chernova, Alasdair D. Keith, Meredith Keen, Abigail Saltzman, Ana Martinez Gascueña, Beatriz Trastoy, Marcelo E. Guerin, Filipp Frank, Eric A. Ortlund, Jeffrey V. Ravetch and Eric J. Sundberg ()
Additional contact information
Diego E. Sastre: Emory University School of Medicine
Stylianos Bournazos: The Rockefeller University
Maros Huliciak: Emory University School of Medicine
Barbara Ann C. Grace: The Rockefeller University
E. Josephine Boder: The Rockefeller University
Jonathan Du: Emory University School of Medicine
Nazneen Sultana: Emory University School of Medicine
Tala Azzam: Emory University School of Medicine
Trenton J. Brown: Emory University School of Medicine
Maria W. Flowers: Emory University School of Medicine
Pete Lollar: Emory University School of Medicine
Ting Xu: Emory University School of Medicine
Tatiana A. Chernova: Emory University School of Medicine
Alasdair D. Keith: Emory University School of Medicine
Meredith Keen: Emory University School of Medicine
Abigail Saltzman: Emory University School of Medicine
Ana Martinez Gascueña: Biobizkaia Health Research Institute
Beatriz Trastoy: Biobizkaia Health Research Institute
Marcelo E. Guerin: Department of Structural and Molecular Biology; Molecular Biology Institute of Barcelona (IBMB)
Filipp Frank: Emory University School of Medicine
Eric A. Ortlund: Emory University School of Medicine
Jeffrey V. Ravetch: The Rockefeller University
Eric J. Sundberg: Emory University School of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract Corynebacterium diphtheriae clade species secrete single-domain endo-β-N-acetylglucosaminidases (ENGases) that specifically bind to human IgG antibodies and hydrolyze their N297-linked glycans. Here, we define the molecular mechanisms of IgG-specific deglycosylation for the entire family of corynebacterial IgG-specific ENGases, including but not limited to CU43 and CM49. By solving the crystal structure of CU43 in a 1:1 complex with the IgG1 Fc region, combined with targeted and saturation mutagenesis analysis and activity measurements using engineered antibodies, we establish an inter-protomeric mechanism of recognition and deglycosylation of IgG antibodies. Using in silico modeling, small-angle X-ray scattering and saturation mutagenesis we determine that CM49 uses a unique binding site on the Fc region, to process N297-linked glycans. Moreover, we demonstrate that CU43 treatment is highly effective in abrogating Fc effector functions in humanized mouse models, while preserving the neutralizing capacity of anti-influenza IgG antibodies, thereby conferring protection against lethal influenza challenge.

Date: 2025
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-025-60986-w Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-60986-w

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-025-60986-w

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().