guthridge-structureofthegm-2008.pdf (1.9 MB)
The structure of the GM-CSF receptor complex reveals a distinct mode of cytokine receptor activation
journal contribution
posted on 2008-08-08, 00:00 authored by Guido Hansen, Timothy R Hercus, Barbara J McClure, Frank C Stomski, Mara Dottore, Jason Powell, Hayley Ramshaw, Joanna M Woodcock, Yibin Xu, Mark GuthridgeMark Guthridge, William J McKinstry, Angel F Lopez, Michael W ParkerGranulocyte-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.
History
Journal
CellVolume
134Issue
3Pagination
496 - 507Publisher
Cell PressLocation
Cambridge, Mass.Publisher DOI
Link to full text
ISSN
0092-8674eISSN
1097-4172Language
engPublication classification
C1 Refereed article in a scholarly journalCopyright notice
2008, ElsevierUsage metrics
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