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

激活参与宿主防御的产生活性氧的吞噬细胞 NADPH 氧化酶的分子机制。

基本信息

批准号：
16390081
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：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-16390081/
关键词：
protein lipid signal transduction infectious disease immunology enzyme NADPH oxidase

项目摘要

Enzymes called NADPH oxidases produce reactive oxygen species, which play a crucial role in host defense. The catalytic center of the phagocyte NADPH oxidase, the prototype of these enzymes, exists in the membrane protein gp91^<phox>, which is complexed with p22^<phox> to form cytochrome b_<558>. Activation of gp91^<phox> results from stimulus-induced membrane translocation of the specific adaptor proteins p47^<phox>, p67^<phox>, and p40^<phox>, which targeting leads to interaction with the cytochrome. During these two years, we have investigated the mechanism for activation of NADPH oxidases and obtained the following findings.(1)It is known that the membrane translocation of p47^<phox> requires its interaction with p22^<phox>. We have shown that the interaction is mediated by a novel mode of recognition by the p47^<phox> SH3 domains. In addition, we have determined the NMR structure of the complex of the p47^<phox> SH3 domains with a peptide of p22^<phox>.(2)The p47^<phox>-p67^<phox> … More interaction is known to be essential for the membrane translocation of p67^<phox>. We have demonstrated that phosphorylation of Ser-379 in p47^<phox> results in attenuation of the p47^<phox>-p67^<phox> interaction, thereby regulating activation of the phagocyte NADPH oxidase.(3)We have identified the amino acids 151-153 of p47^<phox> as residues that participate in oxidase activation by interacting with gp91^<phox>.(4)The gp91^<phox> homologue Nox1 is considered to play an important role in host defense by colon epithelial cells. We have revealed that the small GTPase Rac is directly involved in activation of Nox:Rac functions by facilitating membrane localization of Noxa1,a homologue of p67^<phox>, and by inducing a conformational change of Noxa1. We have also shown that Nox3,the gp91^<phox> homologue expressed in the inner ear, forms a heterodimer with p22^<phox>, and Nox3 activity is enhanced by p47^<phox>, Noxo1,or p67^<phox>, the former two of which act by interacting with p22^<phox>. Less

被称为NADPH氧化酶的酶产生活性氧，这在宿主防御中起着至关重要的作用。吞噬细胞NADPH氧化酶的催化中心，这些酶的原型，存在于膜蛋白gp 91 ^中<phox>，其与p22^<phox>复合形成细胞色素B_<558>。gp 91 ^的激活<phox>由特异性衔接蛋白p47^、p67^和p40^的刺激诱导的膜易位引起<phox><phox><phox>，其靶向导致与细胞色素的相互作用。在这两年中，我们研究了NADPH氧化酶的活化机制，并获得了以下结果。(1)It已知p47 β的膜转位<phox>需要其与p22 β的相互作用<phox>。我们已经证明，这种相互作用是由p47^SH 3结构域的一种新的识别模式介导<phox>的。此外，我们还测定了p47^<phox>SH 3结构域与p22^肽复合物的NMR结构<phox>。（2）p47^<phox>-p67^<phox> ...更多信息已知相互作用对于p67 β的膜转位是必需的<phox>。我们已经证明，p47^中Ser-379的磷酸化<phox>导致p47^<phox>-p67^<phox>相互作用减弱，从而调节吞噬细胞NADPH氧化酶的激活。(3)We已经鉴定p47 β的氨基酸151-153<phox>是通过与gp 91 β相互作用参与氧化酶活化的残基<phox>。（4）gp 91 ^<phox>同源物Nox 1被认为在结肠上皮细胞的宿主防御中起重要作用。我们已经发现，小的GTd-Rac通过促进Noxa 1（p67的同源物）的膜定位和诱导Noxa 1的构象变化直接参与Nox：Rac功能的激活<phox>。我们还发现，在内耳中表达的gp 91 ^同源物Nox 3<phox>与p22^形成异源二聚体<phox>，Nox 3的活性被p47^<phox>、Noxo 1或p67^<phox>增强，前两者通过与p22^相互作用而起作用<phox>。少