Abstract
The nonclassical class I MHC molecule HLA-G is selectively expressed on extravillous cytotrophoblast cells at the maternal-fetal interface during pregnancy. HLA-G can inhibit the killing mediated by NK cells via interaction with the inhibitory NK cell receptor, leukocyte Ig-like receptor-1 (LIR-1). Comparison of the sequence of the HLA-G molecule to other class I MHC proteins revealed two unique cysteine residues located in positions 42 and 147. Mutating these cysteine residues resulted in a dramatic decrease in LIR-1 Ig binding. Accordingly, the mutated HLA-G transfectants were less effective in the inhibition of NK killing and RBL/LIR-1 induced serotonin release. Immunoprecipitation experiments demonstrated the involvement of the cysteine residues in the formation of HLA-G protein oligomers on the cell surface. The cysteine residue located at position 42 is shown to be critical for the expression of such complexes. These oligomers, unique among the class I MHC proteins, probably bind to LIR-1 with increased avidity, resulting in an enhanced inhibitory function of LIR-1 and an impaired killing function of NK cells.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Animals
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Antigens, CD / metabolism
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Antigens, CD / physiology*
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Binding, Competitive / genetics
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Binding, Competitive / immunology
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Cell Line, Transformed
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Cysteine / genetics
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Cysteine / physiology
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Cytotoxicity, Immunologic / genetics
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Decidua / cytology
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Decidua / immunology
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Down-Regulation / genetics
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Down-Regulation / immunology
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Female
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HLA Antigens / biosynthesis
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HLA Antigens / genetics
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HLA Antigens / metabolism
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HLA Antigens / physiology*
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HLA-G Antigens
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Histocompatibility Antigens Class I / biosynthesis
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Histocompatibility Antigens Class I / genetics
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Histocompatibility Antigens Class I / metabolism
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Histocompatibility Antigens Class I / physiology*
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Humans
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Leukocyte Immunoglobulin-like Receptor B1
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Macromolecular Substances
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Membrane Glycoproteins / biosynthesis
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Membrane Glycoproteins / genetics
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Membrane Glycoproteins / metabolism
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Membrane Glycoproteins / physiology*
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Molecular Sequence Data
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Mutagenesis, Site-Directed
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Protein Binding / genetics
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Protein Binding / immunology
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Rats
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Receptors, Immunologic / antagonists & inhibitors
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Receptors, Immunologic / metabolism
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Receptors, Immunologic / physiology*
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Transfection
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Tumor Cells, Cultured
Substances
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Antigens, CD
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HLA Antigens
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HLA-G Antigens
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Histocompatibility Antigens Class I
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LILRB1 protein, human
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Leukocyte Immunoglobulin-like Receptor B1
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Macromolecular Substances
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Membrane Glycoproteins
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Receptors, Immunologic
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Cysteine