Efficient leukocyte Ig-like receptor signaling and crystal structure of disulfide-linked HLA-G dimer
Efficient leukocyte Ig-like receptor signaling and crystal structure of disulfide-linked HLA-G dimer
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DOI：
10.1074/jbc.m512305200
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发表时间：
2006-04-14
影响因子：
4.8
通讯作者：
Maenaka, K
中科院分区：
文献类型：
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作者：
Shiroishi, M;Kuroki, K;Maenaka, K
HLA-G是一种非经典的主要组织相容性复合物I类（MHCI）分子，其在滋养层中表达，并通过结合白细胞Ig样受体（LILR，也称为LIR/ILT/CD 85）和CD 8在母胎界面赋予免疫耐受性。HLA-G在溶液和细胞表面均以二硫键连接的二聚体形式表达。有趣的是，MHCI二聚体的形成参与了发病机制和T细胞活化。MHCI二聚体的结构和受体结合特性从未被评估过。在这里，我们进行的结合研究表明，HLA-G二聚体表现出更高的整体亲和力LILRB 1/2比单体显着的亲合力效应。此外，细胞报告基因分析表明，二聚体的形成显着增强LILRB 1介导的信号在细胞水平上。我们进一步确定了具有分子间Cys（42）-Cys（42）二硫键的野生型HLA-G二聚体的晶体结构。这种二聚体结构显示出倾斜的构型，从而从膜向上暴露两个LILR/CD 8结合位点，易于受体接近，提供了合理的1：2（HLA-G二聚体：受体）复合物模型。这些结果表明，HLA-G二聚体在适当的结构取向上赋予增加的亲合力以诱导有效的LILR信号传导，导致显性免疫抑制作用。此外，还讨论了在激活的T细胞和致病性等位基因HLA-B27中观察到的其他MHCI二聚体的结构和功能影响。
HLA-G is a nonclassical major histocompatibility complex class I (MHCI) molecule, which is expressed in trophoblasts and confers immunological tolerance in the maternal-fetal interface by binding to leukocyte Ig-like receptors (LILRs, also called as LIR/ILT/CD85) and CD8. HLA-G is expressed in disulfide-linked dimer form both in solution and at the cell surface. Interestingly, MHCI dimer formations have been involved in pathogenesis and T cell activation. The structure and receptor binding characteristics of MHCI dimers have never been evaluated. Here we performed binding studies showing that the HLA-G dimer exhibited higher overall affinity to LILRB1/2 than the monomer by significant avidity effects. Furthermore, the cell reporter assay demonstrated that the dimer formation remarkably enhanced the LILRB1-mediated signaling at the cellular level. We further determined the crystal structure of the wild-type dimer of HLA-G with the intermolecular Cys(42)-Cys(42) disulfide bond. This dimer structure showed the oblique configuration to expose two LILR/CD8-binding sites upward from the membrane easily accessible for receptors, providing plausible 1: 2 (HLA-G dimer: receptors) complex models. These results indicated that the HLA-G dimer conferred increased avidity in a proper structural orientation to induce efficient LILR signaling, resulting in the dominant immunosuppressive effects. Moreover, structural and functional implications for other MHCI dimers observed in activated T cells and the pathogenic allele, HLA-B27, are discussed.