Structure and Regulation of Type 1 Protein Phosphatases

1 型蛋白磷酸酶的结构和调控

• 批准号: 6634911
• 负责人: ANNA A DEPAOLI-ROACH
• 金额: $ 33.53万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-01-01 至 2005-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6634911
• 关键词: enzyme activity; enzyme induction /repression; enzyme mechanism; enzyme structure; gene targeting; genetically modified animals; glucose metabolism; glycogen synthase; glycogenesis; hormone regulation /control mechanism; insulin; laboratory mouse; muscle metabolism; muscle proteins; phosphoprotein phosphatase; phosphorylation; protein localization; protein structure function

DESCRIPTION (provided by the applicant): Protein phosphatase type 1 (PP 1) is a major serine/threonine phosphatase that has been implicated in the control of a variety of fundamental cell functions. A common catalytic subunit associates with a large number of PP1-binding proteins whose function is to target the enzyme to different subcellular compartments, to confer substrate specificity and to control activity. A subset of glycogen-targeting subunits has attracted particular attention because of their potential role in the hormonal control of glycogen metabolism by insulin and epinephrine. Of these, RGL and PTG have been implicated in insulin control of muscle glycogen synthase (GS). Recent work from the principal investigator's laboratory, utilizing knockout mice, has shown that RGL is in fact not required for either insulin or epinephrine control of GS in skeletal muscle, but is essential for activation of GS by muscle contraction. Therefore, the molecular mechanism for one of the best established intracellular actions of insulin remains incompletely understood. The principal investigator has detected an insulin-activated phosphatase both in wild type and in RGL knockout mice, indicating that a distinct phosphatase is involved in insulin action. Thus, the specific aims of this proposal are: (1) To characterize the insulin-stimulated glycogen synthase phosphatase and to elucidate the molecular mechanism by which insulin activates the phosphatase; (2) To probe the role of the glycogen-targeting subunit PTG in hormonal control of glycogen metabolism, by the use of muscle specific-knockout mice, and (3) To elucidate the molecular mechanism by which RGL mediates contraction/exercise-induced activation of glycogen synthase. To address these issues, the principal investigator will combine biochemical and molecular biological approaches with in vivo studies using genetically engineered animal models. Completion of these studies will generate important new information about the regulatory mechanisms of some major forms of protein phosphatase. Understanding the mechanism of contraction control of glycogen metabolism is of great relevance to muscle function. Furthermore, advances in our knowledge of insulin action are of central importance to understanding whole body glucose metabolism and its impairment, as in diabetes.

描述（由申请人提供）：1型蛋白磷酸酶（PP 1）是一种 主要的丝氨酸/苏氨酸磷酸酶，其参与了 各种基本的细胞功能。一个共同的催化亚基 有大量的PP 1结合蛋白，其功能是靶向 酶的不同亚细胞区室，赋予底物特异性 并控制活动。糖原靶向亚基的一个子集吸引了 特别注意，因为它们在荷尔蒙控制中的潜在作用， 胰岛素和肾上腺素的糖原代谢。其中，RGL和PTG已被 参与肌肉糖原合酶（GS）的胰岛素控制。最近的工作 主要研究者的实验室利用基因敲除小鼠，已经 表明RGL实际上不是胰岛素或肾上腺素所必需的 控制骨骼肌中的GS，但对于GS的激活是必需的， 肌肉收缩。因此，分子机理为最佳之一 胰岛素的已确定的细胞内作用仍不完全清楚。 主要研究者在两个病例中均检测到胰岛素激活磷酸酶， 在野生型和RGL敲除小鼠中，表明一种独特的磷酸酶 与胰岛素的作用有关因此，这项建议的具体目标是： (1)为了表征胰岛素刺激的糖原合成酶磷酸酶， 阐明胰岛素激活磷酸酶的分子机制; (2)探讨糖原靶向亚基PTG在激素调控中的作用 通过使用肌肉特异性基因敲除小鼠，和（3） 阐明RGL介导的分子机制 收缩/运动诱导的糖原合酶激活。解决这些 问题，主要研究者将结合联合收割机生化和分子 使用基因工程动物进行体内研究的生物学方法 模型完成这些研究将产生重要的新信息 一些主要形式的蛋白磷酸酶的调节机制。 了解糖原代谢的收缩控制机制， 与肌肉功能密切相关。此外，我们在知识上的进步， 胰岛素作用对于了解全身葡萄糖具有中心重要性 代谢及其损害，如糖尿病。