The structure of the GM-CSF receptor complex reveals a distinct mode of cytokine receptor activation.
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.
Hansen
Guido
G
Biota Structural Biology Laboratory, St. Vincent's Institute of Medical Research, 41 Victoria Parade, Fitzroy, Victoria 3065, Australia.
Hercus
Timothy R
TR
McClure
Barbara J
BJ
Stomski
Frank C
FC
Dottore
Mara
M
Powell
Jason
J
Ramshaw
Hayley
H
Woodcock
Joanna M
JM
Xu
Yibin
Y
Guthridge
Mark
M
McKinstry
William J
WJ
Lopez
Angel F
AF
Parker
Michael W
MW
D000595:Amino Acid Sequence; D003461:Crystallography; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000737:chemistry* / Q000378:metabolism*
D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor