PROTEIN DEGRADATION AND CHOLESTEROL REGULATION

描述：HMG-CoA还原酶是一种内质网驻留蛋白，需要 胆固醇的生物合成，其选择性降解发生在受调控的 在哺乳动物细胞和酵母中都是如此。调查员，他作为一名 博士后首次证明HMGCoA调节酵母中的降解，建议 在这里追求遗传学、细胞生物学和生化的结合 HMG辅酶A还原酶在酵母中的降解研究。调查员 已经确定了一类名为HRD(HMGCoA还原酶降解)的基因 基因)，这是调节降解Hmg2p同工酶所必需的 在酵母中，他现在建议测试和完善他的假设 发展起来的。其中一个基因编码蛋白酶体的一个亚单位， 提示蛋白酶体参与内质网蛋白的降解。另外两个 基因是新的，但在现有的数据库中有同源基因。具体地说 目标是：(1)对Hmg2p序列进行完全剖析 负责调节降级的决定因素(2)了解关键 三种HRD基因和蛋白的特征，包括功能 特异性、细胞定位和生化特性(3)测试 蛋白酶体和泛素化在HRD途径中的参与，以及(4) 寻找与Hmg2p调节降解相关的新基因。

DESCRIPTION: HMG-CoA reductase is an ER resident protein required for cholesterol biosynthesis whose selective degradation occurs in a regulated manner in both mammalian cells and in yeast. The investigator, who as a postdoc first demonstrated HMGCoA regulated degradation in yeast, proposes here to pursue a combination of genetic, cell biological and biochemical investigations of HMG CoA reductase degradation in yeast. The investigator has identified a class of genes called HRD (HMGCoA reductase degradation genes) which is required for the regulated degradation of the Hmg2p isozyme in yeast, and he now proposes to test and refine the hypotheses he has developed. One of these genes encodes a subunit of the proteasome, implicating the proteasome in the degradation of ER proteins. The other two genes are novel but have homologs in existing databases. Specifically the aims are: (1) to perform a complete dissection of Hmg2p sequence determinants responsible for regulated degradation (2) to learn the critical features of the three HRD genes and proteins, including functional specificity, cellular location and biochemical properties (3) to test the involvement of the proteasome and ubiquitination in the HRD pathway, and (4) to discover new genes involved in the regulated degradation of Hmg2p.