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.