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    Antigen-Induced Allosteric Changes in a Human IgG1 Fc Increase Low-Affinity Fc? Receptor Binding

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    Author
    Orlandi, C.
    Deredge, D.
    Ray, K.
    Gohain, N.
    Tolbert, W.
    DeVico, A.L.
    Wintrode, P.
    Pazgier, M.
    Lewis, G.K.
    Date
    2020
    Journal
    Structure
    Publisher
    Cell Press
    Type
    Article
    
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    See at
    https://doi.org/10.1016/j.str.2020.03.001
    Abstract
    Antibody structure couples adaptive and innate immunity via Fab (antigen binding) and Fc (effector) domains that are connected by unique hinge regions. Because antibodies harbor two or more Fab domains, they are capable of crosslinking multi-determinant antigens, which is required for Fc-dependent functions through associative interactions with effector ligands, including C1q and cell surface Fc receptors. The modular nature of antibodies, with distal ligand binding sites for antigen and Fc-ligands, is reminiscent of allosteric proteins, suggesting that allosteric interactions might contribute to Fc-mediated effector functions. This hypothesis has been pursued for over 40 years and remains unresolved. Here, we provide evidence that allosteric interactions between Fab and Fc triggered by antigen binding modulate binding of Fc to low-affinity Fc receptors (Fc?R) for a human IgG1. This work opens the path to further dissection of the relative roles of allosteric and associative interactions in Fc-mediated effector functions. Orlandi et al. show that antigen binding to Fab increases binding of IgG1 Fc to low-affinity Fc?R by conformational allostery. Leucine to alanine mutations at positions 234 and 235 in the lower hinge of IgG1 globally alter Fc structure and biological activity by configurational allostery.
    Sponsors
    The research was supported by grant OPP1033109 , Bill and Melinda Gates Foundation (to G.K.L.) as well as NIH grants R01AI087181 (to G.K.L.), 5P01AI120756 (to A.L.D., G.K.L., and G. Tomaras PI), P01AI124912 (to A.L.D., G.K.L., and R. Gallo PI), R01AI116274 (to M.P.), R01AI129769 (to M.P.), and R01AI150447 (to K.R.).
    Keyword
    antigen binding
    configurational allostery
    conformational allostery
    Fc receptor binding
    Fc-effector function
    HDX-MS
    IgG1 LALA variants
    immunoglobulin
    RFADCC Assay
    Identifier to cite or link to this item
    https://www.scopus.com/inward/record.uri?eid=2-s2.0-85082977077&doi=10.1016%2fj.str.2020.03.001&partnerID=40&md5=e40ec925c493c9b9496a704934624ffb; http://hdl.handle.net/10713/12611
    ae974a485f413a2113503eed53cd6c53
    10.1016/j.str.2020.03.001
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    UMB Open Access Articles 2020

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