Structural basis for recognition of the nonclassical MHC molecule HLA-G by the leukocyte Ig-like receptor B2 (LILRB2/LIR2/ILT4/CD85d)
Structural basis for recognition of the nonclassical MHC molecule HLA-G by the leukocyte Ig-like receptor B2 (LILRB2/LIR2/ILT4/CD85d)
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DOI：
10.1073/pnas.0605228103
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发表时间：
2006-10-31
影响因子：
11.1
通讯作者：
Maenaka, Katsumi
中科院分区：
文献类型：
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作者：
Shiroishi, Mitsunori;Kuroki, Kimiko;Maenaka, Katsumi
HLA-G是一种非经典的MHC I类（MHCI）分子，可抑制母胎界面的广泛免疫反应。人抑制性免疫受体白细胞Ig样受体（LILR）B1 [也称为LIR 1、Ig样转录物2（ILT 2）或CD 85 j]和LILRB 2（LIR 2/ILT 4/CD 85 d）优先识别HLA-G。HLA-G固有地表现出各种形式，包括无β（2）-微球蛋白（β（2）m）和二硫键连接的二聚体形式。值得注意的是，LILRB 1不能识别HLA-G或HLA-B27的β（2）m-游离形式，但LILRB 2可以识别HLA-B27的β（2）m-游离形式。迄今为止，HLA-G/LILR识别的结构基础仍有待研究。在这里，我们报告了LILRB 2/HLA-G复合物的2.5-A分辨率晶体结构。LILRB 2与LILRB 1相比表现出重叠但不同的MHCI识别模式，并且主要识别HLA-G α 3结构域的疏水位点。NMR结合研究也证实了这些LILR识别β（2）m的确认（重链/肽/β（2）m）和游离形式的差异。使用无β 2 m的MHCI的结合研究揭示了不同的β 2 m依赖性LILR结合特异性。这些结果表明，LILRB家族成员之间的细微结构差异导致对各种形式的HLA-G和其他MHCI的不同结合特异性，这反过来可能调节免疫抑制。
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 lg-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 alpha 3 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.