2001 Fiscal Year Final Research Report Summary
Molecular mechanism for activation of the phagocyte NADPH oxidase involued in host defense
| Project/Area Number |
12470028
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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 Medical Institute of Bioregulation, Kyushu University, Prof., 生体防御医学研究所, 教授 (30179303)
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| Co-Investigator(Kenkyū-buntansha) |
KURIBAYASHI Futoshi Graduate School of Medical Scinse, Kyushu University, Res. Associate, 大学院・医学研究院, 助手 (60251443)
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| Project Period (FY) |
2000 – 2001
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| Keywords | host defense / NADPH oxidase / cytochrome b 553 / protein-protein interaction / p47^<phox> / p67^<phox> / p40^<phox> |
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| Research Abstract |
The enzymatic core of the phagocyte NADPH oxidase, that participates in host defense, is cytochrome b_<558> in the membrane. Activation of this enzyme requires stimulus-induced membrane translocation of SH3 domain containing cytosolic proteins, namely p47^<phox>, p67^<phox>, and p40^<phox> to interact with cytochrome b_<558>. We studied mechanism for the oxidase activation obtained the following results.
(1) We determined the three-dimensional structure of the PX/PB2 domain a novel module that we had found in the N-termini of p47^<phox> and p40^<phox>. Furthermore, we found that the PX/PB2 domain has an activity to bind to phosphoinositides, and that the PX domain of p47^<phox> is essential for membrane translocation of this protein and activation of the NADPH oxidase. In addition, we also clarified that the lipid-binding activity of the p47^<phox> PX domain is negatively regulated by intramolecular interaction with its SH3 domains.
(2) We found that p40^<phox> associates with p67^<phox> in resting phagocytes via a novel protein-protein interaction : the PB1 domain of p67^<phox> recognizes and binds to the PC motif of p40^<phox>. We also clarified that this modular interaction also occurs in Bem1p and Cdc24p, signaling proteins in the budding yeast, and plays a crucial role in polarity establishment, and determined the three-dimensional structure of the PB1 domain of Bem1p. Although the role of p40^<phox> had remained unknown, our study revealed that p40^<phox> enhances membrane translocation of p67^<phox> and P47^<phox> via the PB1-PC interaction with p67^<phox>, thereby positively regulating activation of the phagocyte NADPH oxidase.
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