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Elucidation of Activation Mechanism of Granulocyte Colony-Stimulating Factor Receptor

Research Project

Project/Area Number 17570101
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Structural biochemistry
Research InstitutionJapan Atomic Energy Agency

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)

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)
Project Period (FY) 2005 – 2006
Project Status Completed (Fiscal Year 2006)
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)
KeywordsGranulocyte Colony-Stimulating Factor / Activation Mechanism of Receptor / X-ray Crystallography
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.

Report

(3 results)
  • 2006 Annual Research Report   Final Research Report Summary
  • 2005 Annual Research Report
  • Research Products

    (8 results)

All 2006 2005

All Journal Article (8 results)

  • [Journal Article] Homodimeric cross-over structure of the human granulocyte colony-stimulating factor (GCSF) receptor signaling complex2006

    • Author(s)
      玉田 太郎
    • Journal Title

      Proceedings of National Academy of Science of the United States of America 103・9

      Pages: 3135-3140

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary 2005 Annual Research Report
  • [Journal Article] 顆粒球コロニー刺激因子受容体の活性化機構2006

    • Author(s)
      玉田 太郎
    • Journal Title

      日本結晶学会誌 48・6

      Pages: 429-435

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Homodimeric cross-over structure of the human granulocyte colony-stimulating factor (GCSF) receptor signaling complex2006

    • Author(s)
      TAMADA, Taro
    • Journal Title

      Proceedings of National Academy of Science of the United States of America 103-9

      Pages: 3135-3140

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Activation mechanism of granulocyte colony-stimulating factor receptor2006

    • Author(s)
      TAMADA, Taro
    • Journal Title

      Journal of the Crystallographic Society of Japan 48-6

      Pages: 429-435

    • NAID

      10018467452

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] 顆粒球コロニー刺激因子受容体の活性化機構2006

    • Author(s)
      玉田太郎
    • Journal Title

      日本結晶学会誌 48・6

      Pages: 429-435

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Crystallization of a 2 : 2 complex of granulocyte-colony stimulating factor (GCSF) with the ligand-binding region of the GCSF receptor2005

    • Author(s)
      本庄 栄二郎
    • Journal Title

      Acta Crystallographica Section F 61・8

      Pages: 788-790

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Crystallization of a 2 : 2 complex of granulocyte-colony stimulating factor (GCSF) with the ligand-binding region of the GCSF receptor2005

    • Author(s)
      HONJO, Eijiro
    • Journal Title

      Acta Crystallographica Section F 61-8

      Pages: 788-790

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Crystallization of a 2:2 complex of granulocyte-colony stimulating factor (GCSF) with the ligand-binding region of the GCSF receptor2005

    • Author(s)
      本庄 栄二郎
    • Journal Title

      Acta Crystallographica Section F 61・8

      Pages: 788-790

    • Related Report
      2005 Annual Research Report

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Published: 2005-04-01   Modified: 2016-04-21  

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