Structural determinants of unique properties of human IgG4-Fc

J Mol Biol. 2014 Feb 6;426(3):630-44. doi: 10.1016/j.jmb.2013.10.039. Epub 2013 Nov 6.


Human IgG4, normally the least abundant of the four subclasses of IgG in serum, displays a number of unique biological properties. It can undergo heavy-chain exchange, also known as Fab-arm exchange, leading to the formation of monovalent but bispecific antibodies, and it interacts poorly with FcγRII and FcγRIII, and complement. These properties render IgG4 relatively "non-inflammatory" and have made it a suitable format for therapeutic monoclonal antibody production. However, IgG4 is also known to undergo Fc-mediated aggregation and has been implicated in auto-immune disease pathology. We report here the high-resolution crystal structures, at 1.9 and 2.35 Å, respectively, of human recombinant and serum-derived IgG4-Fc. These structures reveal conformational variability at the CH3-CH3 interface that may promote Fab-arm exchange, and a unique conformation for the FG loop in the CH2 domain that would explain the poor FcγRII, FcγRIII and C1q binding properties of IgG4 compared with IgG1 and -3. In contrast to other IgG subclasses, this unique conformation folds the FG loop away from the CH2 domain, precluding any interaction with the lower hinge region, which may further facilitate Fab-arm exchange by destabilisation of the hinge. The crystals of IgG4-Fc also display Fc-Fc packing contacts with very extensive interaction surfaces, involving both a consensus binding site in IgG-Fc at the CH2-CH3 interface and known hydrophobic aggregation motifs. These Fc-Fc interactions are compatible with intact IgG4 molecules and may provide a model for the formation of aggregates of IgG4 that can cause disease pathology in the absence of antigen.

Keywords: 4-morpholineethanesulfonic acid; C1q; FAE; Fab-arm exchange; Fc receptor; IgG4-RD; IgG4-related disease; MES; antibody; immunoglobulin; rFc; recombinant IgG4-Fc; sdFc; serum-derived IgG4-Fc.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Monoclonal / metabolism*
  • Binding Sites
  • Crystallography, X-Ray
  • Humans
  • Immunoglobulin Fab Fragments / metabolism*
  • Immunoglobulin Fc Fragments / chemistry*
  • Immunoglobulin Fc Fragments / metabolism
  • Immunoglobulin G / chemistry*
  • Immunoglobulin G / metabolism*
  • Models, Molecular
  • Protein Structure, Tertiary
  • Receptors, IgG / metabolism*
  • Recombinant Proteins / chemistry*
  • Recombinant Proteins / metabolism


  • Antibodies, Monoclonal
  • Immunoglobulin Fab Fragments
  • Immunoglobulin Fc Fragments
  • Immunoglobulin G
  • Receptors, IgG
  • Recombinant Proteins

Associated data

  • PDB/4C54
  • PDB/4C55