The Structure of the GM-CSF Receptor Ternary Complex Reveals a New Mode of Cytokine Receptor Activation.

Granulocyte-macrophage colony stimulating factor (GM-CSF) is a pleiotropic cytokine that controls the production and function of blood cells, is deregulated in multiple diseases such as asthma, arthritis and leukaemia yet offers therapeutic value in Crohn’s disease and as an adjuvant in anti-cancer therapy. Its receptors are heterodimers consisting of a ligand-specific alpha subunit and a beta subunit which is critical for signalling and is shared with the interleukin (IL)-3 and IL-5 receptors. The latter have also been implicated in pathologies such as acute myeloid leukaemia and allergic inflammation respectively. Despite the clear involvement of this family of receptors in human diseases their three dimensional structures in complex with the cognate ligand is not known and the mechanism by which they signal has remained an enigma. In particular it has baffled scientists that the membrane proximal domains of the beta subunit are 120A apart, too big a distance to allow transphosphorylation of the receptors by their associated JAK-2 kinases and receptor activation. We report here the structure of the human GM-CSF/GM-CSF receptor ternary complex and its assembly into hexamers (comprising 2 molecules of GM-CSF, alpha subunits and beta subunits each) and into unexpected dodecamers or higher order complexes. The dodecamer arrangement allows the interaction of two hexamers through a distinct site 4 which is composed of both alpha and beta subunits. Importantly, mutagenesis of the GM-CSF receptor at the dodecamer interface revealed that whilst site 4 is not involved in high or low affinity binding of ligand it is critical for receptor activation and signalling. This novel form of receptor assembly likely applies also to the IL-3 and IL-5 receptors, providing a structural basis for understanding cytokine receptor activation and for the development of novel therapeutics.