Structural determinants of unique properties of human IgG4-Fc

DOI: 10.1016/j.jmb.2013.10.039
PMID: 24211234

Authors: Anna M. Davies (King's College London; Medical Research Council and Asthma UK Centre in Allergic Mechanisms of Asthma) , Theo Rispens (Sanquin Research; University of Amsterdam) , Pleuni Ooijevaar-De Heer (Sanquin Research; University of Amsterdam) , Hannah J. Gould (King's College London; Medical Research Council and Asthma UK Centre in Allergic Mechanisms of Asthma) , Roy Jefferis (University of Birmingham) , Rob C. Aalberse (Sanquin Research; University of Amsterdam) , Brian J. Sutton (King's College London; Medical Research Council and Asthma UK Centre in Allergic Mechanisms of Asthma)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Molecular Biology

State: Published (Approved)
Published: November 2013

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.

Journal Keywords: Monoclonal; Binding; Crystallography; X-Ray; Humans; Immunoglobulin; Models; Molecular; Protein; Tertiary; Receptors; IgG; Recombinant Proteins

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I03-Macromolecular Crystallography

Added On: 10/01/2014 10:42

Documents:
1-s2.0-S0022283613006967-main.pdf

Discipline Tags:

Health & Wellbeing Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)