Chemical and structural analysis of an antibody folding intermediate trapped during glycan biosynthesis
Human IgG Fc glycosylation modulates immunological effector functions such as antibody-dependent cellular cytotoxicity and phagocytosis. Engineering of Fc glycans therefore enables fine-tuning of the therapeutic properties of monoclonal antibodies. The N-linked glycans of Fc are typically complex-ty...
| Main Authors: | , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
American Chemical Society
2012
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| _version_ | 1826271795677757440 |
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| author | Bowden, T Baruah, K Coles, C Harvey, D Yu, X Song, B Stuart, D Aricescu, A Scanlan, C Jones, E Crispin, M |
| author_facet | Bowden, T Baruah, K Coles, C Harvey, D Yu, X Song, B Stuart, D Aricescu, A Scanlan, C Jones, E Crispin, M |
| author_sort | Bowden, T |
| collection | OXFORD |
| description | Human IgG Fc glycosylation modulates immunological effector functions such as antibody-dependent cellular cytotoxicity and phagocytosis. Engineering of Fc glycans therefore enables fine-tuning of the therapeutic properties of monoclonal antibodies. The N-linked glycans of Fc are typically complex-type, forming a network of noncovalent interactions along the protein surface of the Cγ2 domain. Here, we manipulate the mammalian glycan-processing pathway to trap IgG1 Fc at sequential stages of maturation, from oligomannose- to hybrid- to complex-type glycans, and show that the Fc is structurally stabilized following the transition of glycans from their hybrid- to complex-type state. X-ray crystallographic analysis of this hybrid-type intermediate reveals that N-linked glycans undergo conformational changes upon maturation, including a flip within the trimannosyl core. Our crystal structure of this intermediate reveals a molecular basis for antibody biogenesis and provides a template for the structure-guided engineering of the protein-glycan interface of therapeutic antibodies. |
| first_indexed | 2024-03-06T22:02:21Z |
| format | Journal article |
| id | oxford-uuid:4f06077c-53dd-4e36-b0bf-9be13bba144c |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T22:02:21Z |
| publishDate | 2012 |
| publisher | American Chemical Society |
| record_format | dspace |
| spelling | oxford-uuid:4f06077c-53dd-4e36-b0bf-9be13bba144c2022-03-26T16:04:42ZChemical and structural analysis of an antibody folding intermediate trapped during glycan biosynthesisJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:4f06077c-53dd-4e36-b0bf-9be13bba144cEnglishSymplectic Elements at OxfordAmerican Chemical Society2012Bowden, TBaruah, KColes, CHarvey, DYu, XSong, BStuart, DAricescu, AScanlan, CJones, ECrispin, MHuman IgG Fc glycosylation modulates immunological effector functions such as antibody-dependent cellular cytotoxicity and phagocytosis. Engineering of Fc glycans therefore enables fine-tuning of the therapeutic properties of monoclonal antibodies. The N-linked glycans of Fc are typically complex-type, forming a network of noncovalent interactions along the protein surface of the Cγ2 domain. Here, we manipulate the mammalian glycan-processing pathway to trap IgG1 Fc at sequential stages of maturation, from oligomannose- to hybrid- to complex-type glycans, and show that the Fc is structurally stabilized following the transition of glycans from their hybrid- to complex-type state. X-ray crystallographic analysis of this hybrid-type intermediate reveals that N-linked glycans undergo conformational changes upon maturation, including a flip within the trimannosyl core. Our crystal structure of this intermediate reveals a molecular basis for antibody biogenesis and provides a template for the structure-guided engineering of the protein-glycan interface of therapeutic antibodies. |
| spellingShingle | Bowden, T Baruah, K Coles, C Harvey, D Yu, X Song, B Stuart, D Aricescu, A Scanlan, C Jones, E Crispin, M Chemical and structural analysis of an antibody folding intermediate trapped during glycan biosynthesis |
| title | Chemical and structural analysis of an antibody folding intermediate trapped during glycan biosynthesis |
| title_full | Chemical and structural analysis of an antibody folding intermediate trapped during glycan biosynthesis |
| title_fullStr | Chemical and structural analysis of an antibody folding intermediate trapped during glycan biosynthesis |
| title_full_unstemmed | Chemical and structural analysis of an antibody folding intermediate trapped during glycan biosynthesis |
| title_short | Chemical and structural analysis of an antibody folding intermediate trapped during glycan biosynthesis |
| title_sort | chemical and structural analysis of an antibody folding intermediate trapped during glycan biosynthesis |
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