Protein Degradation and Cholesterol Regulation

蛋白质降解和胆固醇调节

• 批准号: 6897666
• 负责人: Randolph Y. Hampton
• 金额: $ 2.58万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-01-01 至 2006-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6897666
• 关键词: HMG coA reductases; cholesterol; endoplasmic reticulum; genetic regulation; proteasome; protein degradation; protein protein interaction; protein structure function; proteomics; ubiquitin; yeasts

HMG-CoA reductase (HMGR) is an ER resident protein required for cholesterol biosynthesis whose selective degradation occurs in a regulated manner in both mammalian cells and in yeast. Regulated degradation of HMGR allows control of the levels of this enzyme in response to changing cellular need for cholesterol pathway products. Although untapped as an axis of clinical modulation, the regulated degradation of HMGR is absolutely specific for HMGR and thus holds promise for devising new strategies for modulation. Furthermore, HMGR is degraded by a poorly-understood pathway of degradation called ER-associated degradation (ERAD), a process that is implicated in management of cellular stress and in the regulation of numerous other medically important proteins. The investigator is studying the conserved mechanisms by which HMGR undergoes regulated degradation, using yeast molecular biology, biochemistry, and forward and reverse genetics to reveal the underlying mechanisms. The work has shown that the ubiquitin proteasome pathway is central to the regulated degradation of HMGR, a mechanism in operation for mammalian HMGR as well. The current goals are to discover all the proteins responsible for regulated degradation, by the isolation and study of HRD genes (Hmg co a Reductase Degradation), that encode the degradation machinery of ERAD, and COD genes (Control Of reductase Degradation), that encode proteins responsible for the coupling of the sterol pathway signals to the stability of HMGR. Current goals are 1) the analysis of discovered HRD and COD genes, 2) characterize the features of the HMGR molecule that allow it to undergo this unique mode of control; 3) develop and exploit methods to isolate new members of each gene class, and 4) reconstitute regulated degradation of HMGR in vitro using the tools and techniques derived from these efforts.

HMG-CoA还原酶（HMGR）是胆固醇生物合成所需的ER驻留蛋白，其选择性降解在哺乳动物细胞和酵母中以受调节的方式发生。 HMGR的调节降解允许控制这种酶的水平，以响应细胞对胆固醇途径产物的需求变化。虽然尚未开发作为临床调节的轴，但HMGR的调节降解对于HMGR是绝对特异性的，因此有希望设计新的调节策略。 此外，HMGR通过称为ER相关降解（ERAD）的降解途径降解，这是一种涉及细胞应激管理和许多其他医学重要蛋白质调节的过程。 研究人员正在研究HMGR进行调节降解的保守机制，使用酵母分子生物学，生物化学以及正向和反向遗传学来揭示潜在的机制。 这项工作已经表明，泛素蛋白酶体途径是HMGR的调节降解的中心，这也是哺乳动物HMGR的一种运作机制。 目前的目标是通过分离和研究编码ERAD降解机制的HRD基因（Hmg co a还原酶降解）和编码负责甾醇途径信号与HMGR稳定性偶联的蛋白质的COD基因（还原酶降解控制）来发现负责调节降解的所有蛋白质。目前的目标是1）分析发现的HRD和COD基因，2）表征HMGR分子的特征，使其能够进行这种独特的控制模式; 3）开发和利用分离每个基因类别的新成员的方法，以及4）使用来自这些努力的工具和技术在体外重建HMGR的调节降解。