Structural determinants of unique properties of human IgG4-Fc.

Abstract

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.

• Authors: Anna M Davies, Theo Rispens, Pleuni Ooijevaar-de Heer, Hannah J Gould, Roy Jefferis, Rob C Aalberse, Brian J Sutton
• Journal: Journal of molecular biology (J Mol Biol) Vol. 426 Issue 3 Pg. 630-44 (Feb 06 2014) ISSN: 1089-8638 [Electronic] Netherlands
• PMID: 24211234 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

Chemical References

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

Topics

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