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2002 Fiscal Year Final Research Report Summary

Structural biology of tyrosine kinese signaling

Research Project

Project/Area Number 13480208
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Functional biochemistry
Research InstitutionOsaka University

Principal Investigator

OKADA Masato  Research Institute for Microbial Diseases, Professor, 微生物病研究所, 教授 (10177058)

Co-Investigator(Kenkyū-buntansha) KIMURA Yoshiaki  Biomolecular Engineering Research Institute, Group leader, 主席研究員
TSUKIHARA Tomitake  Institute for Protein Research, Professor, たんぱく質研究所, 教授 (00032277)
Project Period (FY) 2001 – 2002
KeywordsSrc / Csk / crystal structure / tyrosine kinases / cell signaling / Cbp / SH2ドメイン / SH3ドメイン
Research Abstract

The carboxyl-terminal Src kinase (Csk) is an indispensable negative regulator for the Src family tyrosine kinases (SFKs) that play pivotal roles in various cell signalings. To understand the molecular basis of Csk-mediated regulation of SFKs, we elucidated the crystal structure of full-length Csk. The Csk crystal consists of six molecules classified as active or inactive states according to the coordinations of catalytic residues. Csk assembles the SH2 and SH3 domains differently from inactive SFKs, and their binding pockets are oriented outward enabling the intermolecular interaction. In active molecules, the SH2-kinase and SH2-SH3 linkers are tightly stuck to the N-lobe of the kinase domain to stabilize the active conformation, and there is a direct linkage between the SH2 and the kinase domains. In inactive molecules, the SH2 domains are rotated destroying the linkage to the kinase domain. Cross-correlation matrices for the active molecules reveal that the SH2 domain and the N-lobe of the kinase domain move as a unit. These observations suggest that Csk can be regulated through coupling of the SH2 and kinase domain and that Csk provides a novel built-in activation mechanism for cytoplasmic tyrosine kinases.

  • Research Products

    (10 results)

All Other

All Publications (10 results)

  • [Publications] Ogawa, A.: "Structure of the carboxyl-terminal Src kinase, Csk"J.Biol.Chem.. 277. 14351-14354 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Lowry, WE.: "Csk a critical link of g protein signals to actin cytoskeletal reorganization"Dev.Cell. 6. 733-744 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Itoh, K.: "Negative regulation of immune synapse formation by anchoring lipid raft to cytoskeleton through Cbp-EBP5O-ERM assembly"J.Immunol.. 168. 541-544 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kono, H.: "Spatial raft coalescence represents an initial step in Fc gamma R signaling"J.Immunol.. 169. 193-203 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Hirose, T.: "Distinct roles of the Src family kinases, SRC-1 and KIN-22, that are negatively regulated by CSK-1 in C. elegans"FEBS Lett.. 534. 133-138 (2003)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Ogawa, A: "Structure of the carboxyl-terminal Src kinase, Csk"J. Biol. Chem. 277. 14351-14354 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Lowry, WE: "Csk, a critical link of g protein signals to actin cytoskeletal reorganization."Dev. Cell. 6. 733-744 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Itoh, K: "Negative regulation of immune synapse formation by anchoring lipid raft to cytoskeleton through Cbp-EBP50-ERM assembly"J. Immunol. 168. 541-544 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kono, H: "Spatial raft coalescence represents an initial step in Fc gamma R signaling."J. Immunol. 169. 193-203 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Hirose, T: "Distinct roles of the Src family kinases,SRC-1and KIN-22, that are negatively regulated by CSK-1 in C. elegans."FEBS Lett. 534. 133-138 (2003)

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 2004-04-14  

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