Abstract
Gp130 is a shared cell-surface signaling receptor for at least ten different hematopoietic cytokines, but the basis of its degenerate recognition properties is unknown. We have determined the crystal structure of human leukemia inhibitory factor (LIF) bound to the cytokine binding region (CHR) of gp130 at 2.5 A resolution. Strikingly, we find that the shared binding site on gp130 has an entirely rigid core, while the LIF binding interface diverges sharply in structure and chemistry from that of other gp130 ligands. Dissection of the LIF-gp130 interface, along with comparative studies of other gp130 cytokines, reveal that gp130 has evolved a "thermodynamic plasticity" that is relatively insensitive to ligand structure, to enable crossreactivity. These observations reveal a novel and alternative mechanism for degenerate recognition from that of structural plasticity.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Antigens, CD / chemistry*
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Antigens, CD / immunology
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Binding Sites / immunology
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Cells, Cultured
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Cross Reactions / immunology
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Crystallography, X-Ray
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Cytokine Receptor gp130
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Cytokines / immunology*
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Eukaryotic Cells / immunology
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Eukaryotic Cells / metabolism
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Growth Inhibitors / chemistry*
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Growth Inhibitors / immunology
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Immunity, Cellular / immunology
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Insecta
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Interleukin-6*
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Leukemia Inhibitory Factor
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Lymphokines / chemistry*
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Lymphokines / immunology
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Macromolecular Substances
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Membrane Glycoproteins / chemistry*
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Membrane Glycoproteins / immunology
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Models, Molecular
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Molecular Structure
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Protein Binding / immunology
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Protein Structure, Tertiary / physiology
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Receptors, Cell Surface / chemistry*
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Receptors, Cell Surface / immunology
Substances
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Antigens, CD
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Cytokines
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Growth Inhibitors
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Interleukin-6
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LIF protein, human
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Leukemia Inhibitory Factor
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Lymphokines
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Macromolecular Substances
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Membrane Glycoproteins
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Receptors, Cell Surface
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Cytokine Receptor gp130