Abstract:
Interleukin (IL)-15 is a member of the small four α-helix bundle family of cytokines. IL-15 was discovered by its ability to mimic IL-2-mediated T-cell proliferation. Both cytokines share the β and γ receptor chains of the IL-2 receptor for signal transduction. However, in addition, they target specific α chain receptors IL-15Rα and IL-2Rα, respectively. The exceptionally high affinity binding of IL-15 to IL-15Rα is mediated by its sushi domain. Here we present the solution structure of the IL-15Rα sushi domain solved by NMR spectroscopy and a model of its complex with IL-15. The model shows that, rather than the familiar hydrophobic forces dominating the interaction interface between cytokines and their cognate receptors, the interaction between the IL-15 and IL-15Rα complex involves a large network of ionic interactions. This type of interaction explains the exceptionally high affinity of the IL-15·IL-15Rα complex, which is essential for the biological effects of this important cytokine and which is not observed in other cytokine/cytokine receptor complexes.