Antigen-Induced Allosteric Changes in a Human IgG1 Fc Increase Low-Affinity Fcγ Receptor Binding
MetadataShow full item record
AbstractAntibody 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.
SponsorsThe 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.).
Fc receptor binding
IgG1 LALA variants
Identifier to cite or link to this itemhttps://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
- An engineered Fc variant of an IgG eliminates all immune effector functions via structural perturbations.
- Authors: Vafa O, Gilliland GL, Brezski RJ, Strake B, Wilkinson T, Lacy ER, Scallon B, Teplyakov A, Malia TJ, Strohl WR
- Issue date: 2014 Jan 1
- Characterization of IgG1 conformation and conformational dynamics by hydrogen/deuterium exchange mass spectrometry.
- Authors: Houde D, Arndt J, Domeier W, Berkowitz S, Engen JR
- Issue date: 2009 Apr 1
- Antibody-receptor interactions mediate antibody-dependent cellular cytotoxicity.
- Authors: Sun Y, Izadi S, Callahan M, Deperalta G, Wecksler AT
- Issue date: 2021 Jul
- Multi-Angle Effector Function Analysis of Human Monoclonal IgG Glycovariants.
- Authors: Dashivets T, Thomann M, Rueger P, Knaupp A, Buchner J, Schlothauer T
- Issue date: 2015
- Global conformational changes in IgG-Fc upon mutation of the FcRn-binding site are not associated with altered antibody-dependent effector functions.
- Authors: Burvenich IJG, Farrugia W, Liu Z, Makris D, King D, Gloria B, Perani A, Allan LC, Scott AM, Ramsland PA
- Issue date: 2018 Jul 5