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Elucidation of Molecular Mechanism of Signal Transduction Mediated by Growth Factor-Receptor System

Research Project

Project/Area Number 05453210
Research Category

Grant-in-Aid for General Scientific Research (B)

Allocation TypeSingle-year Grants
Research Field Structural biochemistry
Research InstitutionTokyo Metropolitan Institute of Medical Science

Principal Investigator

INAGAKI Fuyuhiko  Tokyo Metropolitan Institute of Medical Science Researcher, 生理活性物質研究部門, 研究員 (70011757)

Co-Investigator(Kenkyū-buntansha) OGURA Kenji  Tokyo Metropolitan Institute of Medical Science Researcher, 生理活性物質研究部門, 研究員 (50270682)
HATANAKA Hideki  Tokyo Metropolitan Institute of Medical Science Researcher, 生理活性物質研究部門, 研究員 (00260331)
KOHDA Daisuke  Tokyo Metropolitan Institute of Medical Science Researcher, 生理活性物質研究部門, 研究員 (80186618)
Project Period (FY) 1993 – 1994
Project Status Completed (Fiscal Year 1994)
Budget Amount *help
¥5,600,000 (Direct Cost: ¥5,600,000)
Fiscal Year 1994: ¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 1993: ¥3,800,000 (Direct Cost: ¥3,800,000)
KeywordsNMR / distance geometry / solution structure / erabutoxin b / heregulin alpha / IGF-II / SH3 domain / proline-rich peptide
Research Abstract

We constructed a computer program system to determine the high reolution solution structure of proteins by NMR.The program were applied to determine the structure of heregulin, which is a ligand to ErbB4 receptor which is similar to EGF receptor but is important for regemeration of central nervous system and tumor fotmation. The structure is quite similar to EGF and we expect that heregulin also has similar binding surface to EGF.The patch on the putative receptor binding surface is quite different from that of EGF,supporting that these ligand bind exclusively to cognate receptors. We also determind the solution structure of IGF-II.IGF-II is similar to insulin and IGF-I.We found that the binding sites for insulin/IGF-I receptor and IGF-II receptor are located on the opposite surface of IGF-II.We extended our structural study to the protein interaction in the cytosolic state. SH2 and SH3 are structural module integrated in the signal transduction system. SH2 binds to the activated receptors by the binding to a phosphotyrosine residue in the receptor. Src-homology 3 (SH3) domains mediate signal transduction by binding to proline-rich motifs in target proteins involved in signal transduction system. We have determined the high-resolution structure of the SH3 domains of PLCgamma and Grb2. The three dimensional structure of SH3 domains are quite similar in spite of the low sequence homology (20%). But, owing to low affinity of proline-rich peptide to those SH3 domains, we could not determind the complex structures. Fortunately, VPPPVPPRRR peptide derived from Sos bound to Grb2 N-SH3 with high affinity and we have determined the high-resolution NMR structure of the complex. The NMR data show that the peptide adopts the conformation of a left-handed polyproline type II helix and interacts with three major sites on the SH3 domain. The orientation of the bound peptide is opposite to that of proline-rich peptides bound to the SH3 domains of Abl, Fyn and p85.

Report

(3 results)
  • 1994 Annual Research Report   Final Research Report Summary
  • 1993 Annual Research Report
  • Research Products

    (17 results)

All Other

All Publications (17 results)

  • [Publications] Kohda,D.: "A40-KDa Epidermal Growth Factor/Transforming Growth Factor α-binding Domain Produced by Limited Proteolysis of the Extracellular Domain of the Epidermal Growth Factor Receptor" THE Journal of Biological Chemistry. 268. 1976-1981 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Kohda,D.: "Solution Structure of the SH3 Domain of Phospholipase C-gamma." Cell. 72. 953-960 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Nagata,K.: "Solution Structure of the epidermal growth factor-like domain of heregulin-a,a ligand for p180^<erbB-4>" THE EMBO Journal. 13. 3517-3523 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Kohda,D.: "Solution Structure and ligand-binding site of the C-terminal SH3 domain of GRB2." Structure. 2. 1029-1040 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Terasawa,H.: "Structure of the N-terminal SH3 domain of GRB2 complexed with a peptide from the guanine nucleotide releasing foctor Sos." Nature structural biology. 1. 891-897 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Kohda, D.et.al.: "A 40-kDa Epidermal Growth Factor/transforming-Growth Factor a Binding Domain Produced by Limited Proteolysis of the Extracellular Domain of the Epidermal Growth Factor Receptor." J.Biol.Chem.268. 1976-1981 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Kohda, D.et.al.: "Solution Structure of the SH3 Domain of PLGg" Cell. 72. 953-960 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Nagata, K.et.al.: "Synthesis and solution structure analysis of the EGF-like domain of heregulin-a, a ligand for erbB-4." The EMBO J.13. 3517-3523 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Kohda, D.et.al.: "Solution Structure and ligand-binding site of the Cterminal SH3 domain of GRB2." Structure. 2. 1029-1040 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Terasawa, H.et.al.: "Solution Structure of human insulin-like growth-factor II ; recognition sites for receptor and binding proteins." The EMBO J.13. 1029-1040 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Terasawa, H.et.al.: "Solution Structure of the N-terminal SH3 domain of GRB2 complexed with a peptide from Sos" Nature struc.Biol.1. 891-897 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Kohda,D.: "A4OkDa Epidermal Giowth Foctor/Transforming Growth Foctor α-binding Domain Produced by Limited Protedysis of the Extracellular Domain of the Epdermal Growth Focto Rxq" The Journal of Biological Chemistry. 268. 1976-1981 (1993)

    • Related Report
      1994 Annual Research Report
  • [Publications] Kohda,D.: "Solution Strukture of the SH3 Domain of Phospholipase C-Gamma." Cell. 72. 953-960 (1993)

    • Related Report
      1994 Annual Research Report
  • [Publications] Nagata,K.: "Sdution Structure of the epidermal growth factor-like domain of heregulin-a,a ligand for p180 erbB-4." The EMBO Journal. 13. 3517-3523 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Kohda,D.: "Solution Structure and ligand-birding site of the C-terminal SH3 domain of GRB2." Structure. 2. 1029-1040 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Terasawa,H.: "Structure of the N-terminal SH3 domain of GRB2 complexed with a peptide from the guanine nucleotide releasing factor Sos." Nature structual biology. 1. 891-897 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] D.Kohda: "Solution Structure of the SH3 Domain of PLC-8" Cell. 72. 953-960 (1993)

    • Related Report
      1993 Annual Research Report

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Published: 1993-04-01   Modified: 2016-04-21  

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