title: Cutting Edge: Class II-like Structural Features and Strong Receptor Binding of the Nonclassical HLA-G2 Isoform Homodimer.
abstract: HLA-G is a natural tolerogenic molecule and has the following unique features: seven isoforms (HLA-G1 to HLA-G7), formation of disulfide-linked homodimers, and β2-microglobulin (β2m)-free forms. Interestingly, individuals null for the major isoform, HLA-G1, are healthy and expressed the α2 domain-deleted isoform, HLA-G2, which presumably compensates for HLA-G1 function. However, the molecular characteristics of HLA-G2 are largely unknown. In this study, we unexpectedly found that HLA-G2 naturally forms a β2m-free and nondisulfide-linked homodimer, which is in contrast to the disulfide-bonded β2m-associated HLA-G1 homodimer. Furthermore, single-particle analysis, using electron microscopy, revealed that the overall structure and domain organization of the HLA-G2 homodimer resemble those of the HLA class II heterodimer. The HLA-G2 homodimer binds to leukocyte Ig-like receptor B2 with slow dissociation and a significant avidity effect. These findings provide novel insights into leukocyte Ig-like receptor B2-mediated immune regulation by the HLA-G2 isoform, as well as the gene evolution of HLA classes.
authors.affiliation: Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
authors.forename: Kimiko
authors.initials: K
authors.lastname: Kuroki
authors.affiliation: Advanced Operando-Measurement Technology Open Innovation Laboratory, National Institute of Advanced Industrial Science and Technology, Kashiwanoha 277-8589 Japan.
authors.forename: Kazuhiro
authors.identifier: 0000-0002-1655-8231
authors.initials: K
authors.lastname: Mio
authors.affiliation: Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
authors.forename: Ami
authors.identifier: 0000-0002-0866-2282
authors.initials: A
authors.lastname: Takahashi
authors.affiliation: Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
authors.forename: Haruki
authors.identifier: 0000-0001-6226-8617
authors.initials: H
authors.lastname: Matsubara
authors.affiliation: Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Kasai
authors.affiliation: Advanced Operando-Measurement Technology Open Innovation Laboratory, National Institute of Advanced Industrial Science and Technology, Kashiwanoha 277-8589 Japan.
authors.forename: Sachie
authors.initials: S
authors.lastname: Manaka
authors.affiliation: Department of Cell Biology and Anatomy, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Masahide
authors.identifier: 0000-0001-7656-8194
authors.initials: M
authors.lastname: Kikkawa
authors.affiliation: Graduate School of Engineering, Kobe University, Kobe 650-0047, Japan.|Center for Applied Structural Science, Kobe University, Kobe 650-0047, Japan; and.
authors.forename: Daizo
authors.identifier: 0000-0002-1799-5476
authors.initials: D
authors.lastname: Hamada
authors.affiliation: Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology, Tsukuba 305-8566, Japan.
authors.forename: Chikara
authors.initials: C
authors.lastname: Sato
authors.affiliation: Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan; maenaka@pharm.hokudai.ac.jp.
authors.forename: Katsumi
authors.initials: K
authors.lastname: Maenaka
mesh_terms: D019281:Dimerization; D019143:Evolution, Molecular; D005260:Female; D059951:HLA-G Antigens / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000949:Histocompatibility Antigens Class II / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D056747:Immunomodulation; D008431:Maternal-Fetal Exchange; D008562:Membrane Glycoproteins / Q000378:metabolism*; D011247:Pregnancy; D011485:Protein Binding; D011487:Protein Conformation; D015202:Protein Engineering; D011971:Receptors, Immunologic / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D001613:beta 2-Microglobulin / Q000378:metabolism
chemical_list: D059951:HLA-G Antigens; D000949:Histocompatibility Antigens Class II; C491341:LILRB2 protein, human; D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; D011994:Recombinant Proteins; D001613:beta 2-Microglobulin