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

被引：246
作者：
Hansen, Guido [2 ]
Hercus, Timothy R. [1 ]
McClure, Barbara J. [1 ]
Stomski, Frank C. [1 ]
Dottore, Mara [1 ]
Powell, Jason [1 ]
Ramshaw, Hayley [1 ]
Woodcock, Joanna M. [1 ]
Xu, Yibin [2 ]
Guthridge, Mark [1 ]
McKinstry, William J. [2 ]
Lopez, Angel F. [1 ]
Parker, Michael W. [2 ,3 ]
机构：
[1] Hanson Inst, Inst Med & Vet Sci, Div Human Immunol, Adelaide, SA 5000, Australia
[2] St Vincents Inst Med Res, Biota Struct Biol Lab, Fitzroy, Vic 3065, Australia
[3] Univ Melbourne, Mol Sci & Biotechnol Inst Bio21, Dept Biochem & Mol Biol, Melbourne, Vic 3010, Australia
来源：
CELL | 2008年 / 134卷 / 03期
基金：
美国国家卫生研究院; 英国医学研究理事会; 澳大利亚研究理事会;
关键词：
D O I：
10.1016/j.cell.2008.05.053
中图分类号：
Q5 [生物化学]; Q7 [分子生物学];
学科分类号：
071010 ; 081704 ;
摘要：
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 beta 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.
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收藏
页码：496 / 507
页数：12
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