Shiroishi Mitsunori, Kajikawa Mizuho, Kuroki Kimiko, Ose Toyoyuki, Kohda Daisuke, Maenaka Katsumi
Division of Structural Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
J Biol Chem. 2006 Jul 14;281(28):19536-44. doi: 10.1074/jbc.M603076200. Epub 2006 May 3.
Human leukocyte Ig-like receptor B1 (LILRB1) and B2 (LILRB2) belong to "Group 1" receptors and recognize a broad range of major histocompatibility complex class I molecules (MHCIs). In contrast, "Group 2" receptors show low similarity with LILRB1/B2, and their ligands remain to be identified. To date, the structural and functional characteristics of Group 2 LILRs are poorly understood. Here we report the crystal structure of the extracellular domain of LILRA5, which is an activating Group 2 LILR expressed on monocytes and neutrophils. Unexpectedly, the structure showed large changes in structural conformation and charge distribution in the region corresponding to the MHCI binding site of LILRB1/B2, which are also distinct from killer cell Ig-like receptors and Fc alpha receptors. These changes probably confer the structural hindrance for the MHCI binding, and their key amino acid substitutions are well conserved in Group 2 LILRs. Consistently, the surface plasmon resonance and flow cytometric analyses demonstrated that LILRA5 exhibited no affinities to all tested MHCIs. These results raised the possibility that LILRA5 as well as Group 2 LILRs do not play a role in any MHCI recognition but could possibly bind to non-MHCI ligand(s) on the target cells to provide a novel immune regulation mechanism.
人类白细胞免疫球蛋白样受体B1（LILRB1）和B2（LILRB2）属于“1组”受体，可识别多种主要组织相容性复合体I类分子（MHCIs）。相比之下，“2组”受体与LILRB1/B2的相似性较低，其配体仍有待确定。迄今为止，2组白细胞免疫球蛋白样受体（LILRs）的结构和功能特性仍知之甚少。在此，我们报告了LILRA5胞外域的晶体结构，LILRA5是一种在单核细胞和中性粒细胞上表达的具有激活作用的2组LILR。出乎意料的是，该结构在对应于LILRB1/B2的MHC I结合位点的区域显示出结构构象和电荷分布的巨大变化，这也与杀伤细胞免疫球蛋白样受体和Fcα受体不同。这些变化可能导致了对MHC I结合的结构阻碍，并且它们的关键氨基酸替代在2组LILRs中高度保守。一致地，表面等离子体共振和流式细胞术分析表明，LILRA5对所有测试的MHCIs均无亲和力。这些结果增加了一种可能性，即LILRA5以及2组LILRs在任何MHC I识别中均不起作用，但可能与靶细胞上的非MHC I配体结合，从而提供一种新的免疫调节机制。
