Cutting Edge: Class II-like Structural Features and Strong Receptor Binding of the Nonclassical HLA-G2 Isoform Homodimer

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-de...

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Bibliographic Details
Published in:The Journal of immunology (1950) 2017-05, Vol.198 (9), p.3399-3403
Main Authors: Kuroki, Kimiko, Mio, Kazuhiro, Takahashi, Ami, Matsubara, Haruki, Kasai, Yoshiyuki, Manaka, Sachie, Kikkawa, Masahide, Hamada, Daizo, Sato, Chikara, Maenaka, Katsumi
Format: Article
Language:English
Subjects:
Avidity
beta 2-Microglobulin - metabolism
Dimerization
Electron microscopy
Evolution, Molecular
Female
Histocompatibility antigen HLA
Histocompatibility Antigens Class II - chemistry
Histocompatibility Antigens Class II - metabolism
HLA-G Antigens - chemistry
HLA-G Antigens - genetics
HLA-G Antigens - metabolism
Humans
Immunoglobulins
Immunomodulation
Immunoregulation
Isoforms
Maternal-Fetal Exchange
Membrane Glycoproteins - metabolism
Pregnancy
Protein Binding
Protein Conformation
Protein Engineering
Receptors, Immunologic - metabolism
Recombinant Proteins - chemistry
Recombinant Proteins - genetics
Recombinant Proteins - metabolism
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Summary: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.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.1601296