Shiroishi Mitsunori, Kuroki Kimiko, Rasubala Linda, Tsumoto Kouhei, Kumagai Izumi, Kurimoto Eiji, Kato Koichi, Kohda Daisuke, Maenaka Katsumi
Division of Structural Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
Proc Natl Acad Sci U S A. 2006 Oct 31;103(44):16412-7. doi: 10.1073/pnas.0605228103. Epub 2006 Oct 20.
HLA-G is a nonclassical MHC class I (MHCI) molecule that can suppress a wide range of immune responses in the maternal-fetal interface. The human inhibitory immune receptors leukocyte Ig-like receptor (LILR) B1 [also called LIR1, Ig-like transcript 2 (ILT2), or CD85j] and LILRB2 (LIR2/ILT4/CD85d) preferentially recognize HLA-G. HLA-G inherently exhibits various forms, including beta(2)-microglobulin (beta(2)m)-free and disulfide-linked dimer forms. Notably, LILRB1 cannot recognize the beta(2)m-free form of HLA-G or HLA-B27, but LILRB2 can recognize the beta(2)m-free form of HLA-B27. To date, the structural basis for HLA-G/LILR recognition remains to be examined. Here, we report the 2.5-A resolution crystal structure of the LILRB2/HLA-G complex. LILRB2 exhibits an overlapping but distinct MHCI recognition mode compared with LILRB1 and dominantly recognizes the hydrophobic site of the HLA-G alpha3 domain. NMR binding studies also confirmed these LILR recognition differences on both conformed (heavy chain/peptide/beta(2)m) and free forms of beta(2)m. Binding studies using beta(2)m-free MHCIs revealed differential beta(2)m-dependent LILR-binding specificities. These results suggest that subtle structural differences between LILRB family members cause the distinct binding specificities to various forms of HLA-G and other MHCIs, which may in turn regulate immune suppression.
HLA - G是一种非经典的MHC I类（MHCI）分子，可抑制母胎界面的多种免疫反应。人类抑制性免疫受体白细胞免疫球蛋白样受体（LILR）B1[也称为LIR1、免疫球蛋白样转录本2（ILT2）或CD85j]和LILRB2（LIR2/ILT4/CD85d）优先识别HLA - G。HLA - G固有地呈现多种形式，包括无β2 - 微球蛋白（β2m）和二硫键连接的二聚体形式。值得注意的是，LILRB1不能识别无β2m形式的HLA - G或HLA - B27，但LILRB2可以识别无β2m形式的HLA - B27。迄今为止，HLA - G/LILR识别的结构基础仍有待研究。在此，我们报告了LILRB2/HLA - G复合物的2.5埃分辨率晶体结构。与LILRB1相比，LILRB2表现出重叠但不同的MHCI识别模式，并主要识别HLA - G α3结构域的疏水位点。核磁共振结合研究也证实了在β2m的构象形式（重链/肽/β2m）和游离形式上这些LILR识别差异。使用无β2m的MHCIs进行的结合研究揭示了不同的β2m依赖性LILR结合特异性。这些结果表明，LILRB家族成员之间细微的结构差异导致对各种形式的HLA - G和其他MHCIs具有不同的结合特异性，这反过来可能调节免疫抑制。
