title: Structural basis for recognition of the nonclassical MHC molecule HLA-G by the leukocyte Ig-like receptor B2 (LILRB2/LIR2/ILT4/CD85d).
abstract: 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 Ig-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 alpha3 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.
authors.affiliation: Division of Structural Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Mitsunori
authors.initials: M
authors.lastname: Shiroishi
authors.forename: Kimiko
authors.initials: K
authors.lastname: Kuroki
authors.forename: Linda
authors.initials: L
authors.lastname: Rasubala
authors.forename: Kouhei
authors.initials: K
authors.lastname: Tsumoto
authors.forename: Izumi
authors.initials: I
authors.lastname: Kumagai
authors.forename: Eiji
authors.initials: E
authors.lastname: Kurimoto
authors.forename: Koichi
authors.initials: K
authors.lastname: Kato
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kohda
authors.forename: Katsumi
authors.initials: K
authors.lastname: Maenaka
mesh_terms: D015703:Antigens, CD / Q000737:chemistry / Q000276:immunology; D006680:HLA Antigens / Q000737:chemistry* / Q000145:classification / Q000235:genetics / Q000276:immunology*; D015789:HLA-A2 Antigen / Q000737:chemistry / Q000276:immunology; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I / Q000737:chemistry* / Q000145:classification / Q000235:genetics / Q000276:immunology*; D006801:Humans; D000075362:Leukocyte Immunoglobulin-like Receptor B1; D008562:Membrane Glycoproteins / Q000737:chemistry* / Q000235:genetics / Q000276:immunology*; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D011971:Receptors, Immunologic / Q000737:chemistry* / Q000235:genetics / Q000276:immunology*; D040681:Structural Homology, Protein; D020349:Surface Plasmon Resonance; D001613:beta 2-Microglobulin / Q000737:chemistry / Q000276:immunology
chemical_list: D015703:Antigens, CD; D006680:HLA Antigens; D015789:HLA-A2 Antigen; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I; C105299:LILRB1 protein, human; C491341:LILRB2 protein, human; D000075362:Leukocyte Immunoglobulin-like Receptor B1; D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; D001613:beta 2-Microglobulin