Shah Ishan S, Lovell Scott, Mehzabeen Nurjahan, Battaile Kevin P, Tolbert Thomas J
Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, KS, USA.
Protein Structure Laboratory, Del Shankel Structural Biology Center, University of Kansas, Lawrence, KS, USA.
Mol Immunol. 2017 Dec;92:28-37. doi: 10.1016/j.molimm.2017.10.001. Epub 2017 Oct 12.
Immunoglobulin G (IgG) consists of four subclasses in humans: IgG1, IgG2, IgG3 and IgG4, which are highly conserved but have unique differences that result in subclass-specific effector functions. Though IgG1 is the most extensively studied IgG subclass, study of other subclasses is important to understand overall immune function and for development of new therapeutics. When compared to IgG1, IgG3 exhibits a similar binding profile to Fcγ receptors and stronger activation of complement. All IgG subclasses are glycosylated at N297, which is required for Fcγ receptor and C1q complement binding as well as maintaining optimal Fc conformation. We have determined the crystal structure of homogenously glycosylated human IgG3 Fc with a GlcNAcMan (Man5) high mannose glycoform at 1.8Å resolution and compared its structural features with published structures from the other IgG subclasses. Although the overall structure of IgG3 Fc is similar to that of other subclasses, some structural perturbations based on sequence differences were revealed. For instance, the presence of R435 in IgG3 (and H435 in the other IgG subclasses) has been implicated to result in IgG3-specific properties related to binding to protein A, protein G and the neonatal Fc receptor (FcRn). The IgG3 Fc structure helps to explain some of these differences. Additionally, protein-glycan contacts observed in the crystal structure appear to correlate with IgG3 affinity for Fcγ receptors as shown by binding studies with IgG3 Fc glycoforms. Finally, this IgG3 Fc structure provides a template for further studies aimed at engineering the Fc for specific gain of function.
免疫球蛋白G（IgG）在人类中由四个亚类组成：IgG1、IgG2、IgG3和IgG4，它们高度保守，但具有独特差异，导致亚类特异性效应功能。尽管IgG1是研究最广泛的IgG亚类，但研究其他亚类对于理解整体免疫功能和开发新疗法很重要。与IgG1相比，IgG3对Fcγ受体表现出相似的结合谱，并能更强地激活补体。所有IgG亚类在N297处都进行了糖基化，这是Fcγ受体和C1q补体结合以及维持最佳Fc构象所必需的。我们已经确定了均匀糖基化的人IgG3 Fc的晶体结构，其糖型为GlcNAcMan（Man5）高甘露糖型，分辨率为1.8Å，并将其结构特征与其他IgG亚类已发表的结构进行了比较。尽管IgG3 Fc的整体结构与其他亚类相似，但基于序列差异揭示了一些结构扰动。例如，IgG3中R435（其他IgG亚类中为H435）的存在被认为导致了与IgG3与蛋白A、蛋白G和新生儿Fc受体（FcRn）结合相关的特性。IgG3 Fc结构有助于解释其中一些差异。此外，晶体结构中观察到的蛋白质-聚糖接触似乎与IgG3对Fcγ受体的亲和力相关，这在与IgG3 Fc糖型的结合研究中得到了证实。最后，这种IgG3 Fc结构为进一步旨在工程化Fc以实现特定功能增益的研究提供了模板。
