2003 Fiscal Year Final Research Report Summary
Molecular mechanism for activation of the reactive-oxygen-species-producing phagocyte NADPH oxidaae that is involved in host defense
| Project/Area Number |
14370046
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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 |
General medical chemistry
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| Research Institution | Kyushu University |
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Principal Investigator |
SUMIMOTO Hideki Kyushu University, Medical Institute of Bioregulation, Professor, 生体防御医学研究所, 教授 (30179303)
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| Co-Investigator(Kenkyū-buntansha) |
TAKEYA Ryu Kyushu University, Medical Institute of Bioregulation, Research Associate, 生体防御医学研究所, 助手 (50335981)
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| Project Period (FY) |
2002 – 2003
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| Keywords | protein / lipid / signal transduction / Infectious disease / Immunology / enzyme / NADPH oxidase |
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| Research Abstract |
The NADPH oxidase is an enzyme that produces reactive oxygen species, which play a crucial role in host defense. The catalytic core of the phagocyte NADPH oxidase is membrane-integrated cytochrome fb_<558>, comprising gp91^<phox> and p22^<phox>. Activation of the oxidase requires stimulus-induced membrane translocation of specific adaptor proteins(p47^<phox>,p67^<phox>, and p0^<phox>, each containing SH3 domain) : they interact with the cytochrome at the membrane. In the present project, we investigated the molecular mechanism for the oxidase activation, and obtained the following novel findings, (1)We have shown that p47^<phox> binds to p22^<phox> via the two SH3 domains in a manner where they recognize one proline-rich region(PRR) of p22^<phox> ; this interaction is essential for the oxidase activation. (2)We have revealed that the phosphoinositide-binding activity of the PX domain of p47^<phox> is required for activation of the phagocyte oxidase. (3)We have shown that p67^<phox> interacts with p47^<phox> via the C-terminal SH3 domain in a novel fashion, and determined the NMR structure of a complex between the p67^<phox> SH3 domain and the p47^<phox> PRR. (4)We have demonstrated that p40^<phox> facilitates the oxidase activation by enhancing the membrane translocation of p47^<phox> and p67^<phox> which effect is mediated via its interaction with p67^<phox>. (5)We have identified and cloned novel homologues of p47^<phox> and p67^<phox>, designated p41^<nox> and p51^<nox>, respectively, and shown that p41^<nox> and p51^<nox> can activate not only gp91^<phox> but also Nox1.
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[Publications] Kuribayashi, F., Nunoi, H., Wakamatsu, K., Tsunawaki, S., Sato, K., Ito, T., Sumimoto.H.: "The adaptor protein p40^<phox> as a positive regulator of the superoxide-producing phagocyte oxidase."EMBO J.. 21. 6312-6320 (2002)
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「研究成果報告書概要(欧文)」より
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[Publications] Ago, T., Kuribayashi, F., Hiroaki, H., Takeya, R., Ito, T., Kohda, D., Sumimoto.H.: "Phosphorylation of p47^<phox> directs phox homology domain from SH3 domain toward phosphoinositides, leading to phagocyte NADPH oxidase activation."Proc.Natl.Acad.Sci.USA. 100. 4474-4479 (2003)
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「研究成果報告書概要(欧文)」より
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[Publications] Takeya, R., Ueno, N., Kami, K., Taura, M., Kohjima, M., Izaki, T., Nunoi, H., Sumimoto.H.: "Novel human homologues of p47^<phox> and p67^<phox> participate in activation of superoxide-producing NADPH oxidases."J.Biol.Chem.. 278. 25234-25246 (2003)
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「研究成果報告書概要(欧文)」より
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[Publications] Yoshinaga, S., Kohjima, M., Ogura, K., Yokochi, M., Takeya.R., Ito, T., Sumimoto.H., Inagaki, F.: "The FB1 domain and the PC motif-containing region are structurally similar protein binding modules."EMBO J.. 22. 4888-4897 (2003)
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「研究成果報告書概要(欧文)」より
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[Publications] Kami, K., Takeya.R., Sumimoto, H.: "Identification of functional domains and residues. In Methods hi Protein Science at the Postsequence Era vol.4(Ohshima, T., Suzuki, K., Fujii, Y., and Muramatsu, T., eds.)(in Japanese)."Tokyo Kagaku Dohjin. 73-88 (2003)
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「研究成果報告書概要(欧文)」より
