title: Crystal structure of the mouse interleukin-3 β-receptor: insights into interleukin-3 binding and receptor activation.
abstract: 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 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 granulocyte/macrophage colony-stimulating factor (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. In the present study, we have solved the crystal structure of the βIL-3 ectodomain at 3.45 Å (1 Å=0.1 nm) 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 with 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 capacity for direct interaction and specificity.
authors.affiliation: *Research School of Chemistry, Australian National University, Acton 0200, Australia.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Carr
authors.affiliation: †John Curtin School of Medical Research, Australian National University, Acton 0200, Australia.
authors.forename: Cameron L
authors.initials: CL
authors.lastname: Ewens
authors.affiliation: †John Curtin School of Medical Research, Australian National University, Acton 0200, Australia.
authors.forename: Jin
authors.initials: J
authors.lastname: Dai
authors.affiliation: *Research School of Chemistry, Australian National University, Acton 0200, Australia.
authors.forename: David L
authors.initials: DL
authors.lastname: Ollis
authors.forename: James M
authors.initials: JM
authors.lastname: Murphy
authors.affiliation: *Research School of Chemistry, Australian National University, Acton 0200, Australia.
authors.forename: Colin J
authors.initials: CJ
authors.lastname: Jackson
authors.affiliation: †John Curtin School of Medical Research, Australian National University, Acton 0200, Australia.
authors.forename: Ian G
authors.initials: IG
authors.lastname: Young
mesh_terms: D000818:Animals; D018360:Crystallography, X-Ray; D053648:Cytokine Receptor Common beta Subunit / Q000737:chemistry* / Q000378:metabolism; D019143:Evolution, Molecular; D007377:Interleukin-3 / Q000737:chemistry* / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D011487:Protein Conformation; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry
chemical_list: D053648:Cytokine Receptor Common beta Subunit; D007377:Interleukin-3; D011994:Recombinant Proteins