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Structural Biology of Phagocyte oxidation

吞噬细胞氧化的结构生物学

基本信息

批准号：
14208076
负责人：
INAGAKI Fuyuhiko
金额：
$ 32.86万
依托单位：
Hokkaido University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-14208076/
关键词：
phagocyte oxidation system protein-protein interaction SH3 domain activation mechanism auto inhibition p47 tandem SH3 domains PRR peptide 新規NMR技術

项目摘要

The phagocyte NADPH oxidase, a defense system for microbial infection comprises membrane bound flavocytochrome cyt b_<558> (gp91^<phox> and p22^<phox>) and cytosolic factors including p67^<phox>, p47^<phox>, p40^<phox> and small GTPase Rac. Upon microbial invasion, the cytosolic factors are translocated to the membrane to bind to cyt b_<558>, which activates a redox-core of cyt b_<558> and generates O_2-, a precursor of microbicidal oxidants. The activation of the NADPH oxidase is tightly regulated through conformation change of the tandem SH3 domain of p47^<phox>.Recently, the crystal structure of the tandem SH3 domains in the autoinhibited form (Groemping et al., Cell,2003, Yuzawa et al., Genes Cells,2004, J Biol Chem.,2004) and the activated form (Groemping et al., Cell,2003) were determined. Interestingly, the tandem SH3 domains formed an intertwisted dimer in the crystal state but the splitted half was considered to be physiologically relevent. Here, we report the three dimensional structures of the masked and unmasked states of the tandem SH3 domains by NMR. Furthermore, we elucidated the global conformation change of the tandem SH3 domains from the masked to unmasked states by small angle X-ray scattering. Based on the present structural data, we discussed the activation mechanism of the phagocyte NADPH oxidase.

吞噬细胞NADPH氧化酶是一种微生物感染的防御系统，由膜结合的黄色素细胞色素B_<558>（gp 91 ^<phox>和p22^<phox>）和胞浆因子p67^<phox>、p47^<phox>、p40^<phox>和小G蛋白Rac组成。当微生物侵入时，胞浆因子移位到细胞膜上与细胞色素B_结合<558>，激活细胞色素B_的氧化还原核心<558>，产生O_2-，即杀菌氧化剂的前体。NADPH氧化酶的活化通过p47 α的串联SH 3结构域的构象变化而受到严格调节<phox>。最近，自抑制形式的串联SH 3结构域的晶体结构（Groemping等人，Cell，2003，Yuzawa等人，Genes Cells，2004，J Biol Chem.，2004）和活化形式（Groemping等，Cell，2003）测定。有趣的是，串联的SH 3结构域在晶体状态下形成相互扭曲的二聚体，但分裂的一半被认为是生理相关的。在这里，我们报告的三维结构的屏蔽和非屏蔽状态的串联SH 3域的NMR。此外，我们阐明了整体构象变化的串联SH 3域从掩蔽到未掩蔽状态的小角X射线散射。根据目前的结构数据，我们讨论了吞噬细胞NADPH氧化酶的激活机制。