1. Structural and Functional Basis for LILRB Immune Checkpoint Receptor Recognition of HLA-G Isoforms
- Author
-
Haruki Matsubara, Hideo Fukuhara, Yuko Fukunaga, Yuji Sugita, Mitsunori Shiroishi, Katsumi Maenaka, R. Kanda, Atsushi Fukunaga, Joan S. Hunt, Toyoyuki Ose, Shunsuke Kita, Naoyuki Miyashita, Kaoru Hirose, Jun Kamishikiryo, and Kimiko Kuroki
- Subjects
Models, Molecular ,Gene isoform ,Protein Conformation ,Immunology ,Plasma protein binding ,Human leukocyte antigen ,Molecular Dynamics Simulation ,Ligands ,Structure-Activity Relationship ,03 medical and health sciences ,0302 clinical medicine ,LILRB2 ,HLA-G ,Humans ,Protein Isoforms ,Immunology and Allergy ,Receptors, Immunologic ,Binding site ,Receptor ,HLA-G Antigens ,Binding Sites ,Chemistry ,Immune checkpoint ,Cell biology ,Multiprotein Complexes ,beta 2-Microglobulin ,Protein Binding ,030215 immunology - Abstract
Human leukocyte Ig-like receptors (LILR) LILRB1 and LILRB2 are immune checkpoint receptors that regulate a wide range of physiological responses by binding to diverse ligands, including HLA-G. HLA-G is exclusively expressed in the placenta, some immunoregulatory cells, and tumors and has several unique isoforms. However, the recognition of HLA-G isoforms by LILRs is poorly understood. In this study, we characterized LILR binding to the β2-microglobulin (β2m)-free HLA-G1 isoform, which is synthesized by placental trophoblast cells and tends to dimerize and multimerize. The multimerized β2m-free HLA-G1 dimer lacked detectable affinity for LILRB1, but bound strongly to LILRB2. We also determined the crystal structure of the LILRB1 and HLA-G1 complex, which adopted the typical structure of a classical HLA class I complex. LILRB1 exhibits flexible binding modes with the α3 domain, but maintains tight contacts with β2m, thus accounting for β2m-dependent binding. Notably, both LILRB1 and B2 are oriented at suitable angles to permit efficient signaling upon complex formation with HLA-G1 dimers. These structural and functional features of ligand recognition by LILRs provide novel insights into their important roles in the biological regulations.
- Published
- 2019