Crystal structure of the mouse interleukin-3 β-receptor: insights into interleukin-3 binding and receptor activation

Interleukin-3 (IL-3) is a cytokine secreted by mast cells and activated T-cells known to be an important regulator of differentiation, survival, proliferation and activation of a range of haemopoietic lineages. The effects of IL-3 on target cells are mediated by a transmembrane receptor system composed of a cytokine-specific a-subunit and a beta-subunit, the principal signalling entity. In the mouse, two beta-subunits have co-evolved: a common beta-subunit (beta c) shared between IL-3 and the related cytokines IL-5 and granulocyte/macrophage colony-stimulating factor (GM-CSF); and an IL-3-specific beta-subunit (beta(IL-3)). beta(IL-3) differs from fic in its specificity for IL-3 and its capacity to bind IL-3 directly in the absence of an a-subunit, and, in the absence of structural information, the basis for these properties has remained enigmatic. In the present study, we have solved the crystal structure of the beta(IL-3) ectodomain at 3.45 A (1 A = 0.1 nm) resolution. This structure provides the first evidence that PHA adopts an arch-shaped intertwined homodimer with similar topology to the paralogous Pc structure. In contrast with beta c, however, the ligand-binding interface of beta(IL-3) appears to preexist in a conformation receptive to IL-3 engagement. Molecular modelling of the IL-3 P3 interface, in conjunction with previous mutational studies, suggests that divergent evolution of both beta(IL-3) and IL-3 underlies their unique capacity for direct interaction and specificity.