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Structures of the Four Ig-Like Domain LILRB2 and the Four-Domain LILRB1

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Structures of the Four Ig-Like Domain LILRB2 and the Four-Domain LILRB1 www.nature.com/cmi Cellular & Molecular Immunology ARTICLE Structures of the four Ig-like domain LILRB2 and the four- domain LILRB1 and HLA-G1 complex Qihui Wang 1,2, Hao Song3, Hao Cheng3, Jianxun Qi4, Gol Nam4, Shuguang Tan4, Junzhi Wang5, Min Fang 4, Yi Shi 4,6, Zhigang Tian7, Xuetao Cao8,9, Zhiqiang An2, Jinghua Yan 1,4,10 and George F. Gao 3,4,6,11,12 Leukocyte immunoglobulin (Ig)-like receptors (LILRs), also known as CD85 and immunoglobulin-like transcripts (ILTs), play pivotal roles in regulating immune responses. These receptors define an immune checkpoint that immune therapy can target. Through cis or trans interactions with human leukocyte antigen (HLA)-G, the two most abundantly expressed inhibitory LILRs, LILRB1, and LILRB2 (LILRB1/2, also known as CD85j/d and ILT2/4), are involved in immunotolerance in pregnancy and transplantation, autoimmune diseases, and immune evasion by tumors. Although the discrete domains of LILRB1/2 are clear, the assembly mode of the four extracellular Ig-like domains (D1, D2, D3, and D4) remains unknown. Previous data indicate that D1D2 is responsible for binding to HLA class I (HLA-I), but the roles of D3D4 are still unclear. Here, we determined the crystal structure of the four Ig-like domain LILRB2 and four-domain LILRB1 in complex with HLA-G1. The angles between adjacent domains and the staggered assembly of the four domains suggest limited flexibility and limited plasticity of the receptors during ligand binding. The complex structure of four- domain LILRB1 and HLA-G1 supports the model that D1D2 is responsible for HLA-I binding, while D3D4 acts as a scaffold. Accordingly, cis and trans binding models for HLA-I binding to LILRB1/2 are proposed. The geometries of LILRB1/2 in complex with dimeric and monomeric HLA-G1 suggest the accessibility of the dimeric receptor, which in turn, transduces more inhibitory signals. The assembly of LILRB1/2 and its binding to HLA-G1 could aid in the design of immune regulators and benefit immune interference. Keywords: LILRB1; LILRB2; HLA-G; checkpoint; structural studies Cellular & Molecular Immunology (2020) 17:966–975; https://doi.org/10.1038/s41423-019-0258-5 INTRODUCTION which have been summarized in several excellent reviews.1–3 Leukocyte immunoglobulin-like receptors (LILRs/LIRs), also called Among the ligands of LILRB1/2, human leukocyte antigen class I immunoglobulin-like transcripts (ILTs) and CD85, are a family of (HLA-I) is the most widely expressed. Upon binding to HLA-Is, receptors that regulate immune reactions and play pivotal roles in LILRB1/2 generally inhibit the activities of immune cells, including immunological homeostasis. Activating LILRs (LILRAs) contain a antigen-presenting cells (APCs),4 CD8+ T cells5 and B cells.4,6 short cytoplasmic tail and are associated with the adaptor molecule Moreover, LILRB1 inhibits the polarization of NK cell lytic granules FcεRγ, which has an immunoreceptor tyrosine-based activation and therefore the cytotoxicity of NK cells in response to target motif (ITAM).1 By contrast, inhibitory LILRs (LILRBs) have an cells expressing HLA-I (in trans binding).4,7,8 LILRB1/2 also immunoreceptor tyrosine-based inhibitory motif in their cytoplas- associate with HLA-Is expressed on the same cells to regulate mic domain that interacts with tyrosine phosphatases and inhibits mast cell activation and osteoclast development (in cis bind- activating signals.1 Among the five LILRBs identified (LILRB1–5), ing).9,10 Blocking the interaction between LILRB1 and HLA-I LILRB1 (also called LIR1, ILT2, and CD85j), and LILRB2 (also called restores the cytotoxic activity of NK cells11 and potentiates LIR2, ILT4, and CD85d) have been extensively studied.2,3 macrophage phagocytosis of tumor cells.12 In addition to LILRB1 and LILRB2 (LILRB1/2) bind to multiple ligands and are performing important functional regulation of other members in involved in multiple physiological and pathological situations, this family, LILRBs serve as crucial immune checkpoints that, like 1CAS Key Laboratory of Microbial Physiological and Metabolic Engineering, Institute of Microbiology, Chinese Academy of Sciences, 100101 Beijing, China; 2Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, 77030 Houston, TX, USA; 3Research Network of Immunity and Health (RNIH), Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing 100101, China; 4CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, 100101 Beijing, China; 5Key Laboratory of the Ministry of Health for Research on Quality and Standardization of Biotech Products, National Institutes for Food and Drug Control, 100050 Beijing, China; 6Savaid Medical School, University of Chinese Academy of Sciences, 101408 Beijing, China; 7Institute of Immunology and CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, 230027 Hefei, China; 8National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, 200433 Shanghai, China; 9Department of Immunology & Center for Immunotherapy, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, 100005 Beijing, China; 10College of Life Sciences, University of Chinese Academy of Sciences, 100049 Beijing, China; 11Collaborative Innovation Center for diagnosis and treatment of infectious diseases, Zhejiang University, 310003 Hangzhou, China and 12National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention (China CDC), 102206 Beijing, China Correspondence: Qihui Wang ([email protected]) or George F. Gao ([email protected]) These authors contributed equally: Qihui Wang, Hao Song Received: 14 December 2018 Accepted: 14 June 2019 Published online: 4 July 2019 © CSI and USTC 2019 Structures of the four Ig-like domain LILRB2 and the four-domain LILRB1. Q Wang et al. 967 PD-1, PD-L1, and CTLA-4, could be targets for drug development Table 1. Statistics for crystallographic data collection and structure to treat cancers.13 refinement The LILR family contains 13 members, including two pseudo- genes. Except for LILRA3 and LILRB4 which have two domains, LILRB2 LILRB1/HLA-G-RL9 LILRs contain four immunoglobulin (Ig)-like domains in their extracellular part, including one soluble member (LILRA3).2 Data collection Usually, the four domains are named domain D1, D2, D3, and Space group P61 P21 D4 from distal-to-proximal relative to the membrane. Although Cell dimensions LILRs are important regulatory receptors and 20 years have passed since their characterization, whole structures of LILRs with four a, b, c (Å) 172.20, 172.20, 65.60 69.68, 154.68, 98.20 domains have yet to be solved. Previous work has solved the α, β, γ (°) 90.00, 90.00, 120.00 90.00, 102.24, 90.00 structures of discrete domains of LILRB1/2 (D1D2 and D3D4) and Resolution (Å) 50.00–3.80 (3.94–3.80)a 50.00–3.30 (3.42–3.30) – 14 18 b delineated the interaction between D1D2 and HLA-I. How- Rp.i.m. 0.053 (0.519) 0.105 (0.361) ever, the roles of D3D4 of LILRB1/2 in the interaction with HLA are CC 0.980 (0.997) 0.972 (0.995) still under debate. No substantial binding between LILRB1/2 D3D4 1/2 σ and HLA-I has been detected by surface plasmon resonance I/ I 16.83 (1.85) 7.89 (2.38) (SPR).19 Interestingly, variable binding affinities of LILRB2 to HLA- Completeness (%) 99.9 (100.0) 99.9 (99.9) B*3501 and HLA-B*3503 (which differ in residue 114 or 116 being Redundancy 9.8 (10.0) 4.2 (4.2) 20–22 located in the α1α2 domain of HLA-I) have been reported. Refinement Mutated presented peptides in HLA-B27, HLA-A11, B8, and B7 Resolution (Å) 42.75–3.80 45.42–3.30 were also likely to confer enhanced binding affinity to LILRB2 and fl might be related to HIV-1 escape.23,24 Hence, two models have No. re ections 11,011 29,866 25,26 c been proposed: one model is that no interaction exists Rwork/Rfree 0.264/0.287 0.220/0.267 between D3D4 of LILRB2 and HLA-I and the other model is that No. atoms 25,26 D3D4 bend to interact with α1α2 and the peptides. Further Protein 2983 12,038 studies are needed to determine which model best describes the Water –– interaction between LILRB2 and HLA-I. B-factors 1234567890();,: Here, we determined the structure of four-Ig domain LILRB2 and a complex structure of HLA-G1 and LILRB1 containing four Ig-like Protein 89.9 73.8 domains. For the first time, the hinge region angles between the Water –– D2 and D3 domains in LILRB1 and LILRB2 were elucidated and R.m.s. deviations were found to be ~60° and ~50°, respectively. The arrangements Bond lengths (Å) 0.003 0.002 of the four domains in the long axis were determined, and a staggered assembly mode for LILRB1/2 was uncovered. Compared Bond angles (°) 0.702 0.631 with LILRB2, LILRB1 D2D3 displayed more open angles, probably Ramachandran analysis due to the steric hindrance of D3 by W284. In addition, the Favored (%) 99.48 99.66 structure of LILRB1 in complex with HLA-G1 provided the first Allowed (%) 0.52 0.34 direct structural data supporting the model that D1D2 are Outliers (%) 0.00 0.00 responsible for HLA-I binding and D3D4 act as a scaffold. Accordingly, models for HLA-I binding to LILRB1/2 in cis and trans aValues in parentheses are for the highest-resolution shells b = ∑ − 1/2 ∑ − ∑ ∑ are proposed. The geometries of LILRB1/2 in binding to dimeric Rp.i.m. hkl[1/(N 1)] i|Ii <I>|/ hkl iIi, where Ii is the observed and monomeric HLA-G1 indicate more accessibility of LILRB1/2 to intensity and <I> is the average intensity from multiple measurements c = ∑ − ∑ the dimeric form of HLA-G1, leading to the transduction of more Rwork ||Fo| |Fc||/|Fo|, where Fo and Fc are the structure-factor amplitudes from the data and the model, respectively.
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