Disulfide bond-mediated dimerization of HLA-G on the cell surface

Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 01/2003; 99(25):16180-5. DOI: 10.1073/pnas.212643199
Source: PubMed


HLA-G is a nonclassical class I MHC molecule with an unknown function and with unusual characteristics that distinguish it from other class I MHC molecules. Here, we demonstrate that HLA-G forms disulfide-linked dimers that are present on the cell surface. Immunoprecipitation of HLA-G from surface biotinylated transfectants using the anti-beta2-microglobulin mAb BBM.1 revealed the presence of an approximately equal 78-kDa form of HLA-G heavy chain that was reduced by using DTT to a 39-kDa form. Mutation of Cys-42 to a serine completely abrogated dimerization of HLA-G, suggesting that the disulfide linkage formed exclusively through this residue. A possible interaction between the HLA-G monomer or dimer and the KIR2DL4 receptor was also investigated, but no interaction between these molecules could be detected through several approaches. The cell-surface expression of dimerized HLA-G molecules may have implications for HLA-Greceptor interactions and for the search for specific receptors that bind HLA-G.

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    • "Remarkably this receptor is mainly expressed on decidual NK cells, suggesting a delicate role in pregnancy [29]. At variance to ILT2/4, the monomeric/dimeric status of HLA-G has no impact on the binding avidity towards this receptor [23] [24] [34]. Even more, the functional outcome of HLA-G/KIR2DL4 engagement is not easily predictable in an in vivo situation, as KIR2DL4 bears two elements, the one for inhibition in its cytoplasmic tail and the other one for activation in the transmembrane region. "
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    ABSTRACT: HLA-G is a nonclassical HLA class I molecule. In allogeneic situations such as pregnancy or allograft transplantation, the expression of HLA-G has been related to a better acceptance of the fetus or the allograft. Thus, it seems that HLA-G is crucially involved in mechanisms shaping an allogeneic immune response into tolerance. In this contribution we focus on (i) how HLA-G is involved in transplantation and human reproduction, (ii) how HLA-G is regulated by genetic and microenvironmental factors, and (iii) how HLA-G can offer novel perspectives with respect to therapy.
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    • "Besides Cys residues in α2 and α3 domains that allow intramolecular disulphide bonds, HLA-G molecule presents other important Cys residues. Cys42 in α1 domain and Cys147 in α2 domain can form intermolecular disulphide bonds giving rise to HLA-G dimers that can be observed by SDS/PAGE under nonreducing conditions [92]. These structures have been observed for all HLA-G isoforms except HLA-G3 [93]. "
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    • "Consequently, only the HLA-G/ILT2 interaction is taken into consideration since ILT4 binds mostly B2M-free isoforms. Because it was clearly demonstrated that HLA-G dimers carry most if not all of HLA-G immune-inhibitory functions [44–46], it is fair to state that currently, “tolerogenic HLA-G” is “dimeric B2M-associated HLA-G that acts through ILT2.” "
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