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Conformational Plasticity of the Immunoglobulin Fc Domain in Solution

Authors :: Anthony A. Armstrong
Jinquan Luo
Andrew Mahan
Michal Hammel
Soumya G. Remesh
Source :: Remesh, SG; Armstrong, AA; Mahan, AD; Luo, J; & Hammel, M. (2018). Conformational Plasticity of the Immunoglobulin Fc Domain in Solution. Structure, 26(7), 1007-1014.e2. doi: 10.1016/j.str.2018.03.017. Lawrence Berkeley National Laboratory: Retrieved from: http://www.escholarship.org/uc/item/21q3d6wg, Structure (London, England : 1993), vol 26, iss 7
Publication Year :: 2018
Publisher :: Elsevier BV, 2018.
Abstract: © 2018 The Author(s) Fragment crystallizable (Fc) region of immunoglobulin G (IgG) antibody binds to specific Fc receptors (FcγRs) to control antibody effector functions. Currently, engineered specific Fc-FcγR interactions are validated with a static conformation derived from the crystal structure. However, computational evidence suggests that the conformational variability of Fcs plays an important role in receptor recognition. Here we elucidate Fc flexibility of IgG1, IgG2, and IgG1 Fc with mutations (M255Y/S257T/T259E) in solution by small-angle X-ray scattering (SAXS). Measured SAXS profiles and experimental parameters show variations in flexibility between Fc isotypes. We develop and apply a modeling tool for an accurate conformational sampling of Fcs followed by SAXS fitting. Revealed conformational variability of the CH2 domain as low as 10 Å in displacement, illustrates the power of the atomistic modeling combined with SAXS. This inexpensive SAXS-based approach offers to improve the engineering of antibodies for tailoring Fc receptor interactions through altering and measuring Fc flexibility.