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J Biol Chem. 2019 Jul 12;294(28):10789-10806. doi: 10.1074/jbc.RA118.007134. Epub 2019 May 14.

The solution structure of the human IgG2 subclass is distinct from those for human IgG1 and IgG4 providing an explanation for their discrete functions.

Author information

1
From the Institute of Structural and Molecular Biology, Division of Biosciences, University College London, London, WC1E 6BT, United Kingdom.
2
Institute of Structural and Molecular Biology, Birkbeck College, University of London, London, WC1E 7HX, United Kingdom.
3
From the Institute of Structural and Molecular Biology, Division of Biosciences, University College London, London, WC1E 6BT, United Kingdom s.perkins@ucl.ac.uk.

Abstract

Human IgG2 antibody displays distinct therapeutically-useful properties compared with the IgG1, IgG3, and IgG4 antibody subclasses. IgG2 is the second most abundant IgG subclass, being able to bind human FcγRII/FcγRIII but not to FcγRI or complement C1q. Structural information on IgG2 is limited by the absence of a full-length crystal structure for this. To this end, we determined the solution structure of human myeloma IgG2 by atomistic X-ray and neutron-scattering modeling. Analytical ultracentrifugation disclosed that IgG2 is monomeric with a sedimentation coefficient (s 20, w 0) of 7.2 S. IgG2 dimer formation was ≤5% and independent of the buffer conditions. Small-angle X-ray scattering in a range of NaCl concentrations and in light and heavy water revealed that the X-ray radius of gyration (Rg ) is 5.2-5.4 nm, after allowing for radiation damage at higher concentrations, and that the neutron Rg value of 5.0 nm remained unchanged in all conditions. The X-ray and neutron distance distribution curves (P(r)) revealed two peaks, M1 and M2, that were unchanged in different buffers. The creation of >123,000 physically-realistic atomistic models by Monte Carlo simulations for joint X-ray and neutron-scattering curve fits, constrained by the requirement of correct disulfide bridges in the hinge, resulted in the determination of symmetric Y-shaped IgG2 structures. These molecular structures were distinct from those for asymmetric IgG1 and asymmetric and symmetric IgG4 and were attributable to the four hinge disulfides. Our IgG2 structures rationalize the existence of the human IgG1, IgG2, and IgG4 subclasses and explain the receptor-binding functions of IgG2.

KEYWORDS:

analytical ultracentrifugation; antibody; immunoglobulin G (IgG); molecular modeling; neutron-scattering; small-angle X-ray scattering (SAXS)

PMID:
31088911
PMCID:
PMC6635440
[Available on 2020-07-12]
DOI:
10.1074/jbc.RA118.007134

Conflict of interest statement

The authors declare that they have no conflicts of interest with the contents of this article.

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