Three loops of the common gamma chain ectodomain required for the binding of interleukin-2 and interleukin-7.

The common gamma chain (gammac), a subunit of the interleukin (IL)-2, IL-4, IL-7, IL-9, and IL-15 receptors, contributes to both cytokine binding and subsequent signal transduction. Using a model-based site-directed mutagenesis strategy, we have identified residues of the mouse gammac extracellular domain that are required for normal gammac-dependent enhancement of IL-2 and IL-7 binding. One of these sites, Tyr-103, is homologous to key ligand-interacting residues in the growth hormone and erythropoietin receptors, whereas Cys-161, Cys-210, and Gly-211 may function indirectly by maintaining the functional conformation of gammac via formation of an intramolecular disulfide bond. These two cysteines are also required for the integrity of a putative epitope recognized by TUGm2, an antagonistic monoclonal antibody that blocks gammac-dependent cytokine binding and bioactivity. These results are consistent with the involvement of three predicted loops in gammac that contribute to the binding of both IL-2 and IL-7. Mutations in these loops have also been noted in the gammac gene of patients with X-linked severe combined immunodeficiency.