The solution structure of the human IgG2 subclass is distinct from those for human IgG1 and IgG4 providing an explanation for their discrete functions
The solution structure of the human IgG2 subclass is distinct from those for human IgG1 and IgG4 providing an explanation for their discrete functions
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DOI：
10.1074/jbc.ra118.007134
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发表时间：
2019-07-12
影响因子：
4.8
通讯作者：
Perkins, Stephen J.
中科院分区：
文献类型：
--
作者：
Hui, Gar Kay;Gardener, Antoni D.;Perkins, Stephen J.
与IgG 1、IgG 3和IgG 4抗体亚类相比，人IgG 2抗体显示出独特的治疗有用特性。IgG 2是第二丰富的IgG亚类，能够结合人Fc γ RII/Fc γ RIII，但不结合Fc γ RI或补体C1 q。关于IgG 2的结构信息受到缺乏全长晶体结构的限制。为此，我们通过原子X射线和中子散射模型确定了人骨髓瘤IgG 2的溶液结构。超离心分析表明，IgG 2是单体，沉降系数（s20，w 0）为7.2 S。IgG 2二聚体的形成是123，000物理现实的原子模型，通过Monte Carlo模拟进行联合X射线和中子散射曲线拟合，受铰链中正确二硫键的要求约束，导致确定对称的Y形IgG 2结构。这些分子结构与不对称IgG 1和不对称和对称IgG 4的分子结构不同，并归因于四个铰链二硫化物。我们的IgG 2结构合理化的存在，人IgG 1，IgG 2和IgG 4亚类，并解释受体结合功能的IgG 2。
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 Fc gamma RII/Fc gamma RIII but not to Fc gamma RI 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 (s20, w0) of 7.2 S. IgG2 dimer formation was 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.