Crystal structure of the mouse interleukin-3 {beta}-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 hematopoietic lineages. The effects of IL-3 on target cells are mediated by a transmembrane receptor system composed of a cytokine-specific α-subunit and a β-subunit, the principal signalling entity. In the mouse, two β-subunits have co-evolved: a common β-subunit (βc) shared between IL-3 and the related cytokines, IL-5 and GM-CSF; and an IL-3-specific β-subunit (βIL-3). βIL‑3 differs from βc in its specificity for IL-3 and its capacity to bind IL-3 directly in the absence of an α-subunit and, in the absence of structural information, the basis for these properties has remained enigmatic. Here, we present the crystal structure of the βIL-3 ectodomain at 3.45 Å resolution. This structure provides the first evidence that βIL-3 adopts an arch-shaped, intertwined homodimer with similar topology to the paralogous βc structure. In contrast to apo-βc, however, the ligand-binding interface of βIL‑3 appears to pre-exist in a conformation receptive to IL-3 engagement. Molecular modelling of the IL-3:βIL‑3 interface, in conjunction with previous mutational studies, suggests that divergent evolution of both βIL‑3 and IL-3 underlies their unique capacit...

Source: BJ Signal - August 19, 2014 Category: Biochemistry Authors: P D Carr, C L Ewens, J Dai, D L Ollis, J M Murphy, C J Jackson, I G Young Tags: BJ Biomolecules Source Type: research