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Structures of the four Ig-like domain LILRB2 and the four-domain LILRB1 and HLA-G1 complex.

Authors
  • Wang, Qihui1, 2
  • Song, Hao3
  • Cheng, Hao3
  • Qi, Jianxun4
  • Nam, Gol4
  • Tan, Shuguang4
  • Wang, Junzhi5
  • Fang, Min4
  • Shi, Yi4, 6
  • Tian, Zhigang7
  • Cao, Xuetao8, 9
  • An, Zhiqiang10
  • Yan, Jinghua11, 4, 12
  • Gao, George F13, 14, 15, 16, 17
  • 1 CAS Key Laboratory of Microbial Physiological and Metabolic Engineering, Institute of Microbiology, Chinese Academy of Sciences, 100101, Beijing, China. [email protected] , (China)
  • 2 Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, 77030, Houston, TX, USA. [email protected]
  • 3 Research Network of Immunity and Health (RNIH), Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing, 100101, China. , (China)
  • 4 CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, 100101, Beijing, China. , (China)
  • 5 Key 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. , (China)
  • 6 Savaid Medical School, University of Chinese Academy of Sciences, 101408, Beijing, China. , (China)
  • 7 Institute 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. , (China)
  • 8 National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, 200433, Shanghai, China. , (China)
  • 9 Department of Immunology & Center for Immunotherapy, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, 100005, Beijing, China. , (China)
  • 10 Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, 77030, Houston, TX, USA.
  • 11 CAS Key Laboratory of Microbial Physiological and Metabolic Engineering, Institute of Microbiology, Chinese Academy of Sciences, 100101, Beijing, China. , (China)
  • 12 College of Life Sciences, University of Chinese Academy of Sciences, 100049, Beijing, China. , (China)
  • 13 Research Network of Immunity and Health (RNIH), Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing, 100101, China. [email protected] , (China)
  • 14 CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, 100101, Beijing, China. [email protected] , (China)
  • 15 Savaid Medical School, University of Chinese Academy of Sciences, 101408, Beijing, China. [email protected] , (China)
  • 16 Collaborative Innovation Center for diagnosis and treatment of infectious diseases, Zhejiang University, 310003, Hangzhou, China. [email protected] , (China)
  • 17 National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention (China CDC), 102206, Beijing, China. [email protected] , (China)
Type
Published Article
Journal
Cellular and Molecular Immunology
Publisher
Springer Nature
Publication Date
Sep 01, 2020
Volume
17
Issue
9
Pages
966–975
Identifiers
DOI: 10.1038/s41423-019-0258-5
PMID: 31273318
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

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.

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