STRUCTURE AND FUNCTION OF PHAGOCYTE PROTEINS

吞噬细胞蛋白的结构和功能

• 批准号: 6160661
• 负责人: T L LETO
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6160661
• 关键词: NAD(P)H dehydrogenase; bacterial disease; binding proteins; child (0-11); chimeric proteins; chronic granulomatous disease; disease /disorder proneness /risk; enzyme activity; enzyme inhibitors; enzyme structure; gene mutation; human genetic material tag; human subject; human tissue; inflammation; leukocyte oxidative burst; molecular cloning; phagocytes; protein structure function; tissue /cell culture; transfection

This project is exploring structure-function relationships involved in activation and assembly of the microbicidal NADPH oxidase of phagocytes (the respiratory burst). Earlier work has defined four essential oxidase components (p47-phox, p67-phox, p22-phox and gp91-phox) as proteins absent or defective in various forms of chronic granulomatous disease (CGD), a genetic disease characterized by enhanced susceptibility to bacterial and fungal pathogens. Our current efforts are studying mechanisms of regulation of NADPH oxidase and exploring methods for inhibiting NADPH oxidase function by disrupting interactions among oxidase components. We have recently presented a model for oxidase assembly involving multiple SH3 domain interactions between oxidase components. We have now identified two factors that down-regulate oxidase activity by affecting SH3 domain interactions. p40phox disrupts the oxidase by competing with the tail-tail SH3 interaction between p67phox and a proline-rich target in p47phox. Pak is a Rac-regulated protein kinase that binds to the first SH3 domain of p47phox and down-regulates the oxidase in a phosphorylation-dependent manner. In other work we have identified several proline-rich, SH3-binding ligands from combinatorial peptide phage display libraries. These peptides all bind to the first SH3 domain of p47phox and could serve as specific inhibitors of the oxidase. Other work in progress is exploring the roles of several other protein kinases and phospholipases as potential targets for modulating oxidase activity. These studies will provide insights on this important oxygen-dependent host defense system and may aid in the design of drugs that inhibit production of reactive oxygen species, which are thought to have a role in inflammatory disease processes.

该项目正在探索涉及的结构功能关系 吞噬细胞的杀菌型氧化酶的激活和组装 （呼吸爆发）。 较早的工作定义了四个必需品 氧化酶成分（p47-Phox，p67-phox，p22-phox和gp91-phox）作为 在各种形式的慢性肉芽肿的情况下没有蛋白质 疾病（CGD），一种以增强为特征的遗传疾病 对细菌和真菌病原体的敏感性。我们目前的努力 正在研究NADPH氧化酶调节和探索的机制 通过破坏相互作用来抑制NADPH氧化酶功能的方法 在氧化酶成分中。 我们最近提出了一个模型 氧化酶的组装涉及多个SH3结构域之间的相互作用 氧化酶成分。 我们现在已经确定了两个因素 通过影响SH3结构域相互作用来下调氧化酶活性。 P40Phox通过与Tail-Tail SH3竞争来破坏氧化酶 p67phox和p47phox中富含脯氨酸的目标之间的相互作用。 帕克 是一种由RAC调节的蛋白激酶，与第一个SH3结构域结合 p47phox并下调氧化酶 方式。 在其他工作中，我们已经确定了几个脯氨酸富裕的 组合肽噬菌体显示库中的SH3结合配体。 这些肽都与P47phox的第一个SH3结构域结合，可以 用作氧化酶的特异性抑制剂。 正在进行的其他工作是 探索其他几种蛋白激酶和磷脂酶的作用 作为调节氧化酶活性的潜在靶标。 这些研究 将提供有关这一重要氧气的宿主防御的见解 系统并可能有助于设计抑制产生的药物 活性氧，被认为在 炎症性疾病过程。