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|Title:||The interaction of GM-CSF and IL-3 with the common beta chain of their receptors|
|Citation:||Journal of Leukocyte Biology, 1995; 57(5):739-746|
|Abstract:||Human granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin (IL-3) are cytokines active in both normal and abnormal hemopoiesis, inflammation, and immunity. Their biological activity is mediated via receptors that comprise a ligand-specific alpha chain and a beta chain that is common to the GM-CSF, IL-3, and IL-5 receptors. To understand the mechanism of action of GM-CSF and IL-3 in both normal and pathological conditions, we are seeking to define the structural elements required for ligand/receptor and receptor/receptor contact and their role in cellular activation. To this end we have identified a conserved motif in the first helix of GM-CSF, Glu21 that is critical for high affinity binding and biological activity. Charge-reversal mutagenesis of this residue generates a GM-CSF analogue that is devoid of biological activity and can antagonize the activity of wild-type GM-CSF. This probably results from the selective deficiency in interaction with the beta chain of the receptor and suggests that similar antagonists for IL-3 and IL-5 are also feasible. Complementary mutagenesis studies on the receptor beta chain have identified the putative B'-C' loop in the membrane-proximal domain as being critical for the high affinity binding of GM-CSF but not IL-3. Characterization of the specificity of sites of interaction between the ligands and receptors may permit the design of specific or genetic antagonists that may have important therapeutic implications.|
|Keywords:||Humans; Growth Hormone; Granulocyte-Macrophage Colony-Stimulating Factor; Interleukin-3; Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; Receptors, Interleukin-3; Sequence Alignment; Binding Sites; Binding, Competitive; Amino Acid Sequence; Protein Structure, Secondary; Sequence Homology, Amino Acid; Structure-Activity Relationship; Models, Molecular; Molecular Sequence Data|
|Appears in Collections:||Medicine publications|
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