糖原代谢关键蛋白质的结构和功能研究

In most organisms, glucose is an important energy source, and glycogen is the major storage form of glucose. Glycogen metabolism, the inter-conversion between glucose and glycogen, is a basic and essential energy metabolic pathway. In humans defects in the glycogen metabolism is related to diseases including diabetes. A number of proteins play essential roles in the glycogen metabolism. In this proposal, we will carry out structural and functional studies on two of such proteins: the glycogen debranching enzyme (GDE), and the protein phosphatase 1 (PP1) catalytic subunit-G subunit complex, to reveal the molecular mechanism of their function. We have recently determined the crystal structure of GDE, as well as the catalytic mechanism of its catalytic domains. In this proposal we will study the mechanism of its substrate specificity, which plays essential roles in ensuring the two steps of the debranching reaction it catalyzes proceed in the right order, and in activating the enzyme only when needed. We will also study what role the holo-enzyme structure plays in its function. The PP1 G subunits form complexes with the catalytic subunit, recruiting it to the glycogen particle where the substrates are located, and regulating its activity towards specific substrates. In this proposal we will study the mechanism of this interaction and regulation. Our studies will bring a deeper understanding of the glycogen metabolism, and facilitate the development of novel treatments against diabetes and other related diseases.

在多种生物中，葡萄糖是提供能量的重要分子，糖原是葡萄糖的主要存储方式。糖原代谢指葡萄糖与糖原的相互转化，是一个重要的能量代谢通路。人体糖原代谢的紊乱与糖尿病等疾病密切相关。本项目着眼于揭示糖原代谢关键蛋白质糖原去支链酶、蛋白质磷酸酶１催化亚基－Ｇ亚基复合物的功能机理。我们近期揭示了糖原去支链酶的结构和它催化反应的机制。在此基础上，在本项目中我们将着重研究它高度底物特异性的机理，该特性确保它催化的两步反应顺序进行，也对它在正确的时间发挥功能至关重要。我们也将揭示它的全酶结构在它有效发挥机能方面起何作用。蛋白质磷酸酶１的Ｇ亚基与催化亚基结合，招募它到糖原所处位置行使功能，Ｇ亚基也调控催化亚基对糖原代谢相关底物的活性。在本项目中，我们将研究相互作用的机制和调控的机理。本项目的研究将增进对糖原去支链酶、蛋白质磷酸酶1功能机理的认识，和对糖原代谢的理解，也将为糖尿病等相关疾病的防治提供新思路。

在多种生物中，葡萄糖是提供能量的重要分子，糖原是葡萄糖的主要存储方式。糖原代谢指葡萄糖与糖原的相互转化，是一个重要的能量代谢通路。人体糖原代谢的紊乱与糖尿病等疾病密切相关。本项目着眼于揭示糖原代谢关键蛋白质糖原去支链酶、蛋白质磷酸酶１催化亚基－Ｇ亚基复合物的功能机理。在本项目中，我们解析了糖原去支链酶全酶的结构，揭示了其催化反应的分子机制、反应中间产物的传递机制、其对底物的特异性识别的机制、及其各个结构域在反应中如何协作。蛋白质磷酸酶１的Ｇ亚基与催化亚基结合，招募它到糖原所处位置行使功能，Ｇ亚基也调控催化亚基对糖原代谢相关底物的活性。在本项目中，我们揭示了蛋白质磷酸酶１的Ｇ亚基与催化亚基的相互作用机制，及G亚基调控催化亚基的机理。本项目的研究增进了对糖原去支链酶、蛋白质磷酸酶1功能机理的认识，和对糖原代谢的理解，也为糖尿病等相关疾病的防治提供新思路。