Protein Degradation and Cholesterol Regulation

蛋白质降解和胆固醇调节

• 批准号: 6621258
• 负责人: Randolph Y. Hampton
• 金额: $ 28.18万
• 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/6621258
• 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内质网驻留蛋白，其选择性降解在哺乳动物细胞和酵母中都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，以响应不断变化的细胞对胆固醇途径产物的需求。虽然作为临床调节的一个轴尚未开发，但HMGR的调节降解绝对是针对HMGR的，因此有望设计新的调节策略。此外，HMGR通过一种鲜为人知的降解途径被降解，称为er相关降解（ERAD），这一过程涉及细胞应激的管理和许多其他医学上重要的蛋白质的调节。研究者正在研究HMGR经过调控降解的保守机制，利用酵母分子生物学、生物化学、正向和反向遗传学来揭示潜在的机制。这项工作表明，泛素蛋白酶体途径是调节HMGR降解的核心，这一机制也适用于哺乳动物HMGR。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 Reductase degradation）和编码负责将甾醇途径信号偶联到HMGR稳定性的COD基因（Control of Reductase degradation），来发现所有负责调控降解的蛋白质。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，使其能够经历这种独特的控制模式；3)开发和利用分离每个基因类别新成员的方法；4)利用这些努力衍生的工具和技术在体外重建HMGR的调控降解。