Granulocyte-macrophage colony stimulating factor (GM-CSF), interleukin-3 (IL-3) and interleukin-5 (IL-5) are cytokines that regulate the growth, differentiation, migration and effector function activities of many hematopoietic cells. They are involved in normal responses to infectious agents bridging innate and adaptive immunity but over-expression of these cytokines or their receptors can lead to chronic inflammatory diseases and myeloid leukemia’s.

GM-CSF signals through a heterodimeric receptor consisting of a ligand-specific ɑ subunit (GMRɑ) and a β subunit (βc) which is shared with the interleukin-3 and interleukin-5 receptors. We recently determined the crystal structure of the human GM-CSF:GMRɑ:βc ternary complex that revealed a novel mode of receptor activation involving a higher-order dodecamer complex. Based on X-ray diffraction data collected to 2.8 Å resolution we have now generated a complete model of the GM-CSF:GMRɑ binary complex wherein the GMRɑ structure is strikingly reminiscent of the IL-13Rɑ and IL-5Rɑ subunits. We have used mutagenesis, ligand binding and functional studies to examine the contribution of residues in GMRɑ and GM-CSF that form the binding interface and has allowed us to define residues in GM-CSF and GMRɑ involved in receptor complex assembly. Importantly, a novel role for the N-terminal domain of these alpha chains in the signaling of βc family cytokines is apparent. Comparisons of the ligand:alpha chain interactions between GM-CSF, IL-3 and IL-5 is allowing us to identify differences or similarities that define the specificity and affinity of these ligand:receptor interactions that contribute to signaling by these cytokines.