The structure of the GM-CSF receptor complex reveals a distinct mode of cytokine receptor activation

Guido Hansen, Timothy R Hercus, Barbara J McClure, Frank C Stomski, Mara Dottore, Jason A Powell, Hayley S Ramshaw, Joanna M Woodcock, Yibin Xu, Mark Andrew Guthridge, William John McKinstry, Angel F Lopez, Michael William Parker

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196 Citations (Scopus)

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 a subunit and a ?c 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. ? 2008 Elsevier Inc. All rights reserved
Original languageEnglish
Pages (from-to)496 - 507
Number of pages12
JournalCell
Volume134
Issue number3
DOIs
Publication statusPublished - 2008
Externally publishedYes

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