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PROTEIN DEGRADATION AND CHOLESTEROL REGULATION

蛋白质降解和胆固醇调节

基本信息

批准号：
6342482
负责人：
Randolph Y. Hampton
金额：
$ 22.6万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-01-01 至 2001-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6342482
关键词：
HMG coA reductases cholesterol endoplasmic reticulum genetic regulation molecular cloning nucleic acid sequence proteasome protein degradation protein structure function ubiquitin yeasts

项目摘要

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.

描述：HMG-CoA还原酶是一种ER驻留蛋白，胆固醇生物合成，其选择性降解发生在受调节的在哺乳动物细胞和酵母中的方式。作为一名调查员，博士后首先证明了HMGCoA在酵母中调节降解，提出在这里寻求遗传学、细胞生物学和生物化学的结合酵母中HMG CoA还原酶降解的研究。研究者已经确定了一类称为HRD（HMGCoA还原酶降解）的基因基因），其是Hmg2p同工酶的调节降解所需的在酵母中，他现在提出要测试和完善他的假设，开发其中一个基因编码蛋白酶体的一个亚基，提示蛋白酶体参与ER蛋白的降解。另外两基因是新的，但在现有的数据库中有同源物。特别是目的：（1）对Hmg2p序列进行完整的解剖负责调节退化的决定因素（2），以了解关键的三种HRD基因和蛋白质的特征，包括功能特异性、细胞定位和生化特性（3），以测试蛋白酶体和遍在蛋白化参与HRD途径，以及（4）发现参与Hmg2p降解调控的新基因。