Title : The
structure of the GM-CSF receptor complex reveals a distinct mode of cytokine
receptor activation
Abstract :
- Granulocyte-macrophage colony-stimulating factor ( GM-CSF ) is a pleiotropic cytokine that controls the production and function of blood cells, is deregulated in clinical conditions such as rheumatoid arthritis and leukemia, yet offers therapeutic value for other diseases
- Its receptors are heterodimers consisting of a ligand-specific alpha subunit and a betac subunit that is shared with the interleukin ( IL)-3 and IL-5 receptors
- How signaling is initiated remains an enigma
- We report here the crystal structure of the human GM-CSF / GM-CSF receptor ternary complex and its assembly into an unexpected dodecamer or higher-order complex
- Importantly, mutagenesis of the GM-CSF receptor at the dodecamer interface and functional studies reveal that dodecamer formation is required for receptor activation and signaling
- This unusual form of receptor assembly likely applies also to IL-3 and IL-5 receptors , providing a structural basis for understanding their mechanism of activation and for the development of therapeutics
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