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Molecular mechanism for activation of the reactive-oxygen-species-producing phagocyte NADPH oxidaae that is involved in host defense

参与宿主防御的活性氧产生吞噬细胞NADPH氧化酶激活的分子机制

基本信息

批准号：
14370046
负责人：
SUMIMOTO Hideki
金额：
$ 9.6万
依托单位：
Kyushu University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2003
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14370046/
关键词：
protein lipid signal transduction Infectious disease Immunology enzyme NADPH oxidase NDAPHオキシダーゼ

项目摘要

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.

NADPH氧化酶是一种产生活性氧的酶，在宿主防御中起着至关重要的作用。吞噬细胞NADPH氧化酶的催化核心是膜整合的细胞色素fb<558>，包括gp 91 - 1<phox>和p22 - 1<phox>。氧化酶的激活需要刺激诱导的特异性衔接蛋白（p47^<phox>、p67 ^<phox>和p0^<phox>，每个都含有SH 3结构域）的膜转位：它们与膜上的细胞色素相互作用。在本项目中，我们研究了氧化酶激活的分子机制，并获得了以下新的发现：（1）我们已经表明，p47^<phox><phox>通过两个SH 3结构域以识别p22^的一个富含脯氨酸的区域（PRR）的方式与p22^结合<phox>;这种相互作用是氧化酶激活所必需的。(2)We已经揭示了p47 β的PX结构域的磷酸肌醇结合活性<phox>是激活吞噬细胞氧化酶所必需的。(3)We已经表明p67^<phox><phox>通过C-末端SH 3结构域以一种新的方式与p47^相互作用，并确定了p67^<phox>SH 3结构域和p47^<phox>PRR之间复合物的NMR结构。(4)We已经证明，p40 α<phox>通过增强p47 α和p67 α的膜转位而促进氧化酶活化<phox><phox>，该作用是通过其与p67 α的相互作用介导的<phox>。(5)We已经鉴定并克隆了p47^和p67^的新同源物<phox><phox>，分别命名为p41^<nox>和p51^<nox>，并表明p41^<nox>和p51^<nox>不仅可以激活gp 91 ^<phox>，而且可以激活Nox 1。