Structural basis for binding multiple ligands by the common cytokine receptor gamma-chain.
The common gamma-chain (gamma(c)) that functions both in ligand binding and signal transduction is a shared subunit of the multichain receptors for interleukin (IL)-2, IL-4, IL-7, IL-9, IL-15, and IL-21. The structural basis by which the ectodomain of gamma(c) contributes to binding six distinct cytokines is only partially defined. In the present study, epitope mapping of antagonistic anti-gamma(c) monoclonal antibodies led to the identification of Asn-128 of mouse gamma(c) that represents another potential contact residue that is required for binding IL-2, IL-7, and IL-15 but not IL-4. In addition, Tyr-103, Cys-161, Cys-210, and Cys-211, previously identified to contribute to binding IL-2 and IL-7, were also found to be involved in binding IL-4 and IL-15. Collectively, these data favor a model in which gamma(c) utilizes a common mechanism for its interactions with multiple cytokines, and the binding sites are largely overlapping but not identical. Asn-128 and Tyr-103 likely act as contact residues whereas Cys-161, Cys-210, and Gly-211 may stabilize the structure of the proposed ligand-interacting surface formed by the two extracytoplasmic domains.
Olosz
Ferenc
F
Department of Microbiology and Immunology, University of Miami School of Medicine, Miami, Florida 33101, USA.
Malek
Thomas R
TR
D000595:Amino Acid Sequence; D000818:Animals; D001216:Asparagine / Q000737:chemistry; D001483:Base Sequence; D001665:Binding Sites; D019556:COS Cells; D002469:Cell Separation; D003432:Cross-Linking Reagents / Q000494:pharmacology; D003545:Cysteine / Q000737:chemistry; D018076:DNA, Complementary / Q000378:metabolism; D019281:Dimerization; D000939:Epitopes; D005434:Flow Cytometry; D005998:Glycine / Q000737:chemistry; D006801:Humans; D053631:Interleukin Receptor Common gamma Subunit; D019409:Interleukin-15 / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D015851:Interleukin-7 / Q000378:metabolism; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D017354:Point Mutation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051381:Rats; D018121:Receptors, Cytokine / Q000737:chemistry*; D020395:Receptors, Interleukin-7 / Q000737:chemistry*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid; D014162:Transfection; D014443:Tyrosine / Q000737:chemistry
D003432:Cross-Linking Reagents; D018076:DNA, Complementary; D000939:Epitopes; C507941:IL2RG protein, human; C507942:Il2rg protein, mouse; D053631:Interleukin Receptor Common gamma Subunit; D019409:Interleukin-15; D007376:Interleukin-2; D015851:Interleukin-7; D008024:Ligands; D018121:Receptors, Cytokine; D020395:Receptors, Interleukin-7; D015847:Interleukin-4; D014443:Tyrosine; D001216:Asparagine; D003545:Cysteine; D005998:Glycine