Structural characterization of GASDALIE Fc bound to the activating Fc receptor FcγRIIIa
Structural characterization of GASDALIE Fc bound to the activating Fc receptor FcγRIIIa
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DOI：
10.1016/j.jsb.2016.02.001
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发表时间：
2016-04-01
影响因子：
3
通讯作者：
Bjorkman, Pamela J.
中科院分区：
文献类型：
--
作者：
Ahmed, Alysia A.;Keremane, Sravya R.;Bjorkman, Pamela J.
免疫球蛋白G（IgG）的Fc区通过与活化Fc受体（Fc γ RI、Fc γ RIIa、Fc γ RIIIa）结合，引发炎症反应，如抗体依赖性细胞介导的细胞毒性（ADCC）。这些受体在免疫细胞表面表达，包括巨噬细胞、树突细胞和自然杀伤细胞。抑制性受体Fc γ RIIb与活化性受体Fc γ RIIa同时在巨噬细胞和其他髓样白细胞上表达，从而设定细胞活化的阈值。IgG Fc结合活化Fc受体的亲和力取决于IgG亚类和与Fc C（H）2结构域中保守天冬酰胺连接的N-连接聚糖的组成。例如，具有无岩藻糖基化聚糖的Fc区与Fc γ RIIIa的结合比岩藻糖基化Fc更紧密，并且无岩藻糖基化Fc在体内和体外表现出增强的ADCC活性。对于具有氨基酸取代的Fc区，也已经观察到增强的促炎反应。GASDALIE Fc是一种Fc突变体（G236 A/S239 D/A330 L/I332 E），与野生型Fc相比，其对Fc γ RIIIa的亲和力更高，体内效应子功能增加。为了探索其改变的功能，我们比较了GASDALIE和野生型Fc对激活性和抑制性Fc γ R的亲和力。我们还确定了单独的GASDALIE Fc和与Fc γ RIIIa结合的GASDALIE Fc的晶体结构。单独的GASDALIE Fc的总体结构与野生型Fc结构相似，然而，与其他Fc：Fc γ R结构相比，GASDALIE Fc：Fc γ RIIIa界面的静电相互作用增加，表明GASDALIE Fc对Fc γ RIIIa的亲和力增加的机制。(C)2016 Elsevier Inc. All rights reserved.
The Fc region of Immunoglobulin G (IgG) initiates inflammatory responses such as antibody-dependent cell-mediated cytotoxicity (ADCC) through binding to activating Fc receptors (Fc gamma RI, Fc gamma RIIa, Fc gamma RIIIa). These receptors are expressed on the surface of immune cells including macrophages, dendritic cells, and natural killer cells. An inhibitory receptor, Fc gamma RIIb, is expressed on macrophages and other myeloid leukocytes simultaneously with the activating receptor Fc gamma RIIa, thereby setting a threshold for cell activation. The affinity of IgG Fc for binding activating Fc receptors depends on IgG subclass and the composition of N-linked glycans attached to a conserved asparagine in the Fc C(H)2 domain. For example, Fc regions with afucosylated glycans bind more tightly to Fc gamma RIIIa than fucosylated Fc, and afucosylated Fcs exhibit enhanced ADCC activity in vivo and in vitro. Enhanced pro-inflammatory responses have also been seen for Fc regions with amino acid substitutions. GASDALIE Fc is an Fc mutant (G236A/S239D/A330L/I332E) that exhibits a higher affinity for Fc gamma RIIIa and increased effector functions in vivo compared to wild-type Fc. To explore its altered functions, we compared the affinities of GASDALIE and wild-type Fc for activating and inhibitory Fc gamma Rs. We also determined the crystal structure of GASDALIE Fc alone and bound to Fc gamma RIIIa. The overall structure of GASDALIE Fc alone was similar to wild-type Fc structures, however, increased electrostatic interactions in the GASDALIE Fc:Fc gamma RIIIa interface compared with other Fc:Fc gamma R structures suggest a mechanism for the increased affinity of GASDALIE Fc for Fc gamma RIIIa. (C) 2016 Elsevier Inc. All rights reserved.