Conformational Plasticity of the Immunoglobulin Fc Domain in Solution

Structure. 2018 Jul 3;26(7):1007-1014.e2. doi: 10.1016/j.str.2018.03.017. Epub 2018 May 3.

Abstract

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.

Keywords: BILBOMD; SAXS; conformational flexibility; fragment crystallizable (Fc) region; glycoprotein; immunoglobulin G antibody (IgG); rigid body modeling; small angle X-ray scattering.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Crystallography, X-Ray
  • Immunoglobulin Fc Fragments / chemistry*
  • Immunoglobulin G / chemistry*
  • Models, Molecular
  • Protein Binding
  • Protein Conformation
  • Scattering, Small Angle
  • Solubility
  • X-Ray Diffraction

Substances

  • Immunoglobulin Fc Fragments
  • Immunoglobulin G