F. Olosz et Tr. Malek, Three loops of the common gamma chain ectodomain required for the binding of interleukin-2 and interleukin-7, J BIOL CHEM, 275(39), 2000, pp. 30100-30105
The common gamma chain (gamma c), 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 mutagene
sis strategy, we have identified residues of the mouse gamma c extracellula
r domain that are required for normal gamma c-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, w
hereas Cys-161, Cys-210, and Gly-211 may function indirectly by maintaining
the functional conformation of gamma c 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 gamma c-dependent cytokine binding and bioactivity. These resu
lts are consistent with the involvement of three predicted loops in gamma c
that contribute to the binding of both IL-2 and IL-7. Mutations in these l
oops have also been noted in the gamma c gene of patients with X-linked sev
ere combined immunodeficiency.