Elucidation of Activation Mechanism of Granulocyte Colony-Stimulating Factor Receptor
| Project/Area Number |
17570101
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Structural biochemistry
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| Research Institution | Japan Atomic Energy Agency |
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Principal Investigator |
TAMADA Taro Japan Atomic Energy Agency, Quantum Beam Science Directorate, Senior Scientist, 量子ビーム応用研究部門, 研究副主幹 (50391248)
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| Co-Investigator(Kenkyū-buntansha) |
KUROKI Ryota Japan Atomic Energy Agency Quantum Beam Science Directorate, Principal Scientist, 量子ビーム応用研究部門, 研究主幹 (30391246)
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| Project Period (FY) |
2005 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2006: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 2005: ¥2,000,000 (Direct Cost: ¥2,000,000)
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| Keywords | Granulocyte Colony-Stimulating Factor / Activation Mechanism of Receptor / X-ray Crystallography |
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| Research Abstract |
Granulocyte colony-stimulating factor (GCSF) has become an important cytokine for medical treatment of patients suffering from granulopoenia through regulating the maturation, proliferation, and differentiation of the precursor cells of neutrophilic granulocytes. Binding of GCSF to the extracellular Ig-like and CRH domain of its receptor (GCSF-R) triggers receptor homodimerization, resulting in activation of JAK-STAT type signaling cascades. The stoichiometry of the GCSF/GCSF-R complex has been a matter of some debate, with various proposed values (1:1, 2:2 and/or 4:4). Our previous report demonstrated that only the 2:2 stoichiometry is observed as a stable complex.
In this research, we have succeeded in crystallization of 2:2 complex between human GCSF (hGCSF) and the Ig-like and CRH domains of human GCSF-R (hGCSF-R) and determined its tertiary structure by X-ray crystallography at 2.8 A resolution. The signaling 2:2 complex is formed via cross-over interactions between the Ig-like domain of hGCSF-R and the neighboring hGCSF, forming a two-fold axis of crystallographic symmetry. This conformation is quite different from that of the heterogeneous mGCSF-R complex, and more closely resembles the 2:2:2 active assembly of human interleukin-6 (IL-6), human ILr6 a-receptor and human gp 130 (which is a shared signal transducing receptor for several cytokines), and the 2:2 assembly of viral IL-6 and human gp 130. The Ig-like domain cross-over structure necessary for GCSF-R activation is consistent with previously reported thermodynamic and mutational analyses.
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Report
(3 results)
Research Products
(8 results)
