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Type: Journal article
Title: The structure of the GM-CSF receptor complex reveals a distinct mode of cytokine receptor activation
Author: Hansen, G.
Hercus, T.
Mc Clure, B.
Stomski, F.
Dottore, M.
Powell, J.
Ramshaw, H.
Woodcock, J.
Xu, Y.
Guthridge, M.
McKinstry, W.
Lopez, A.
Parker, M.
Citation: Cell, 2008; 134(3):496-507
Publisher: Cell Press
Issue Date: 2008
ISSN: 0092-8674
Statement of
Guido Hansen, Timothy R. Hercus, Barbara J. McClure, Frank C. Stomski, Mara Dottore, Jason Powell, Hayley Ramshaw, Joanna M. Woodcock, Yibin Xu, Mark Guthridge, William J. McKinstry, Angel F. Lopez and Michael W. Parker
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.
Keywords: Humans
Granulocyte-Macrophage Colony-Stimulating Factor
Receptors, Granulocyte-Macrophage Colony-Stimulating Factor
Amino Acid Sequence
Models, Molecular
Molecular Sequence Data
DOI: 10.1016/j.cell.2008.05.053
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