Cell
Volume 134, Issue 3, 8 August 2008, Pages 496-507
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Article
The Structure of the GM-CSF Receptor Complex Reveals a Distinct Mode of Cytokine Receptor Activation

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Summary

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 α subunit and a βc 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.

MOLIMMUNO
SIGNALING

Cited by (0)

4

These authors contributed equally to this work

5

These authors contributed equally to this work

6

Present address: Institute of Biochemistry, Center for Structural and Cell Biology in Medicine, University of Lübeck, 23538 Lübeck, Germany

7

Present address: Structural Biology Division, The Walter and Eliza Hall Institute of Medical Research, Victoria 3050, Australia

8

Present address: CSIRO Molecular and Health Technologies, Parkville, Victoria 3052, Australia