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Deciphering a protein that protects embryos

The survival of our species in the face of high rates of genetic mutation is a significant problem. While mutations provide a source of adaptability to various environments, a large fraction of genetic changes are also damaging. New thoughts about a protein functioning only in fetal cells might help explain not only its function, but its possible use in future immunosuppressive therapies.


Trophoblast cells are found in the outer layer of a developing embryo and form part of its placenta. The cells express a type of protein called human leukocyte antigens-G (HLA-G) which interacts with receptors on the outside of maternal cells to suppress her immune responses to the growing embryo.

Researchers at Hokkaido University together with other colleagues in Japan, have now uncovered the structure of the HLA-G1protein as it protects embryos from their mothers' immune system. Understanding how this protein functions might lead to new immunosuppressive therapies for multiple conditions.

The structure of HLA-G1, the major form of HLA-G, is well understood. But interestingly, individuals whose cells lack HLA-G1 can be born healthy. So researchers believe this may be because these individuals express another form of HLA-G — or HLA-G2 — which could compensate for the loss of HLA-G function. But the structure of HLA-G2 was largely unknown, until this study. Published in the Journal of Immunology, the team investigated the structure of HLA-G2 using a single particle electron microscope.


Surprisingly, the structure of HLA-G2 is completely different from HLA-G1, but similar to another class of human leukocyte antigens called HLA class II. This suggests the HLA-G gene evolved from the same ancestral gene.


The researchers also found that HLA-G2 proteins make pairs called homodimers which strengthen their binding to the maternal cell receptors. HLA-G1 is also known to form homodimers but in a different manner. Both of their biochemical analysis revealed that HLA-G2 bound strongly to a leukocyte immunoglobulin-like receptor B2 (LILRB2), but not to LILRB1. By contrast, HLA-G1 binds strongly to both receptors.


Previous research by the Hokkaido team showed how in addition to its protective role in pregnancy, the HLA-G2 protein has an anti-inflammatory effect when injected into collagen-induced arthritic mice.


"The narrow target specificity of HLA-G2 could be advantageous in developing immunosuppressive drugs with less side-effects. We suggest further investigations to elucidate the structure of the HLA-receptor complex for a more precise understanding of this interaction," adds Katumi Maenaka PhD, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan and corresponding author.

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.

Abbreviations used in this article:
CIA
collagen-induced arthritis
3D
three-dimensional
EM
electron microscopy
LILR
leukocyte Ig-like receptor
β2m
β2-microglobulin
PDB
Protein Data Bank
rsHLA-G2
soluble rHLA-G2
SPR
surface plasmon resonance.

This work was supported in part by the Platform for Drug Discovery, Informatics, and Structural Life Science and Japan Society for the Promotion of Science Grants-in-Aid for Scientific Research KAKENHI (Grants 23770102, 25870019, 16J05871, and 22121007) and by grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan and the Ministry of Health, Labour and Welfare of Japan, including the Program for Advancing Strategic International Networks to Accelerate the Circulation of Talented Researchers, and CREST, Japan Science and Technology. K.K. is supported by the Naito Foundation Subsidy for Female Researchers after Maternity Leave and the Support Office for Female Researchers at Hokkaido University.
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May 17, 2017   Fetal Timeline   Maternal Timeline   News   News Archive   

HLA-G1 protein and a HLA-G2 protein

A comparison of a HLA-G1 protein (left) and a HLA-G2 protein (right), shows significant
structural difference. The HLA-G2 protein shown here is paired in a form called homodimer..
Image Credit: Kuroki K. et al., The Journal of Immunology, March 27, 2017

 


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