2002 Fiscal Year Final Research Report Summary
Structural biology of tyrosine kinese signaling
| Project/Area Number |
13480208
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Functional biochemistry
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| Research Institution | Osaka University |
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Principal Investigator |
OKADA Masato Research Institute for Microbial Diseases, Professor, 微生物病研究所, 教授 (10177058)
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| 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)
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| Project Period (FY) |
2001 – 2002
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| Keywords | Src / Csk / crystal structure / tyrosine kinases / cell signaling / Cbp / SH2ドメイン / SH3ドメイン |
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| 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.
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Research Products
(10 results)
