Mechanism of glycoform specificity and in vivo protection by an anti-afucosylated IgG nanobody
Abstract Immunoglobulin G (IgG) antibodies contain a complex N-glycan embedded in the hydrophobic pocket between its heavy chain protomers. This glycan contributes to the structural organization of the Fc domain and determines its specificity for Fcγ receptors, thereby dictating distinct cellular re...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-05-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-38453-1 |
| _version_ | 1797822713083985920 |
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| author | Aaron Gupta Kevin S. Kao Rachel Yamin Deena A. Oren Yehuda Goldgur Jonathan Du Pete Lollar Eric J. Sundberg Jeffrey V. Ravetch |
| author_facet | Aaron Gupta Kevin S. Kao Rachel Yamin Deena A. Oren Yehuda Goldgur Jonathan Du Pete Lollar Eric J. Sundberg Jeffrey V. Ravetch |
| author_sort | Aaron Gupta |
| collection | DOAJ |
| description | Abstract Immunoglobulin G (IgG) antibodies contain a complex N-glycan embedded in the hydrophobic pocket between its heavy chain protomers. This glycan contributes to the structural organization of the Fc domain and determines its specificity for Fcγ receptors, thereby dictating distinct cellular responses. The variable construction of this glycan structure leads to highly-related, but non-equivalent glycoproteins known as glycoforms. We previously reported synthetic nanobodies that distinguish IgG glycoforms. Here, we present the structure of one such nanobody, X0, in complex with the Fc fragment of afucosylated IgG1. Upon binding, the elongated CDR3 loop of X0 undergoes a conformational shift to access the buried N-glycan and acts as a ‘glycan sensor’, forming hydrogen bonds with the afucosylated IgG N-glycan that would otherwise be sterically hindered by the presence of a core fucose residue. Based on this structure, we designed X0 fusion constructs that disrupt pathogenic afucosylated IgG1-FcγRIIIa interactions and rescue mice in a model of dengue virus infection. |
| first_indexed | 2024-03-13T10:13:11Z |
| format | Article |
| id | doaj.art-0c91ddacfecf4f7fb89461122325693e |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-13T10:13:11Z |
| publishDate | 2023-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-0c91ddacfecf4f7fb89461122325693e2023-05-21T11:20:58ZengNature PortfolioNature Communications2041-17232023-05-0114111110.1038/s41467-023-38453-1Mechanism of glycoform specificity and in vivo protection by an anti-afucosylated IgG nanobodyAaron Gupta0Kevin S. Kao1Rachel Yamin2Deena A. Oren3Yehuda Goldgur4Jonathan Du5Pete Lollar6Eric J. Sundberg7Jeffrey V. Ravetch8Laboratory of Molecular Genetics & Immunology, The Rockefeller UniversityLaboratory of Molecular Genetics & Immunology, The Rockefeller UniversityLaboratory of Molecular Genetics & Immunology, The Rockefeller UniversityStructural Biology Resource Center, The Rockefeller UniversityStructural Biology Program, Memorial Sloan Kettering Cancer CenterDepartment of Biochemistry, Emory University School of MedicineDepartment of Pediatrics, Emory University School of MedicineDepartment of Biochemistry, Emory University School of MedicineLaboratory of Molecular Genetics & Immunology, The Rockefeller UniversityAbstract Immunoglobulin G (IgG) antibodies contain a complex N-glycan embedded in the hydrophobic pocket between its heavy chain protomers. This glycan contributes to the structural organization of the Fc domain and determines its specificity for Fcγ receptors, thereby dictating distinct cellular responses. The variable construction of this glycan structure leads to highly-related, but non-equivalent glycoproteins known as glycoforms. We previously reported synthetic nanobodies that distinguish IgG glycoforms. Here, we present the structure of one such nanobody, X0, in complex with the Fc fragment of afucosylated IgG1. Upon binding, the elongated CDR3 loop of X0 undergoes a conformational shift to access the buried N-glycan and acts as a ‘glycan sensor’, forming hydrogen bonds with the afucosylated IgG N-glycan that would otherwise be sterically hindered by the presence of a core fucose residue. Based on this structure, we designed X0 fusion constructs that disrupt pathogenic afucosylated IgG1-FcγRIIIa interactions and rescue mice in a model of dengue virus infection.https://doi.org/10.1038/s41467-023-38453-1 |
| spellingShingle | Aaron Gupta Kevin S. Kao Rachel Yamin Deena A. Oren Yehuda Goldgur Jonathan Du Pete Lollar Eric J. Sundberg Jeffrey V. Ravetch Mechanism of glycoform specificity and in vivo protection by an anti-afucosylated IgG nanobody Nature Communications |
| title | Mechanism of glycoform specificity and in vivo protection by an anti-afucosylated IgG nanobody |
| title_full | Mechanism of glycoform specificity and in vivo protection by an anti-afucosylated IgG nanobody |
| title_fullStr | Mechanism of glycoform specificity and in vivo protection by an anti-afucosylated IgG nanobody |
| title_full_unstemmed | Mechanism of glycoform specificity and in vivo protection by an anti-afucosylated IgG nanobody |
| title_short | Mechanism of glycoform specificity and in vivo protection by an anti-afucosylated IgG nanobody |
| title_sort | mechanism of glycoform specificity and in vivo protection by an anti afucosylated igg nanobody |
| url | https://doi.org/10.1038/s41467-023-38453-1 |
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