Metabolism of Proteins

蛋白质的代谢

• 批准号: 6749540
• 负责人: ALAN L SCHWARTZ
• 金额: $ 33.66万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-06-01 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6749540
• 关键词: antiserum; cell component structure /function; cell nucleus; cytoplasm; laboratory rabbit; muscle proteins; peptide chemical synthesis; proteasome; protein degradation; protein metabolism; protein structure function; proteolysis; transcription factor; ubiquitin

DESCRIPTION (provided by applicant): Metabolism of proteins is highly regulated in physiological and pathophysiological states such as diabetes, starvation, etc. Both within the whole organism and at the cellular level, proteins exist in a dynamic state, maintained by the relative balance of protein synthesis and degradation. The bulk of cellular protein degradation is via the ubiquitin proteolytic pathway which provides both selectivity and specificity. Herein, cellular proteins via their internal lysine residues are tagged with ubiquitin and degraded via the proteasome. This pathway is responsible for the enhanced proteolysis of skeletal muscle in insulin-dependent diabetes and for the turnover of many regulatory molecules of metabolism including IRS-1 and IRS-2, key components of insulin action. Recent evidence suggests this pathway may exist within the cell nucleus. Our overall hypothesis is that cellular protein degradation is regulated in part by its loci of activity within the cell. In addition, recent data suggest a new targeting pathway for proteolysis with tagging via a protein's N terminus. The aims of the present proposal are thus (1) to analyze the motif, identify the components, and determine the physiological significance of N-terminus dependent ubiquitination of cellular proteins and (2) to define the subcellular sites and mechanisms responsible for protein degradation. These studies will be carried out using a variety of physiological, pharmacological, biochemical, molecular and cellular systems. Ultimately, the ability to modulate protein metabolism in physiological and pathophysiological states requires a detailed mechanistic understanding of the pathways of protein metabolism, the subject of the present proposal.

描述（由申请人提供）：蛋白质的代谢受到生理和病理生理状态（例如糖尿病，饥饿等）的高度调节。无论是在整个生物体内还是在细胞水平上，蛋白质都存在于动态状态，并由蛋白质合成和去分解的相对维持。大部分细胞蛋白降解是通过泛素蛋白水解途径既具有选择性又具有特异性的。在此，通过其内部赖氨酸残基的细胞蛋白用泛素标记，并通过蛋白酶体降解。该途径负责胰岛素依赖性糖尿病中骨骼肌的蛋白水解以及许多代谢的调节分子的周转，包括IRS-1和IRS-2（包括IRS-1和IRS-2），这是胰岛素作用的关键组成部分。最近的证据表明，该途径可能存在于细胞核内。我们的总体假设是细胞蛋白降解部分受细胞中活性基因座的调节。此外，最近的数据表明，通过通过蛋白质的N末端进行标记的蛋白水解的新靶向途径。因此，本提案的目的是（1）分析基序，确定成分并确定N端依赖性依赖性细胞蛋白和（2）的生理意义，以定义负责蛋白质降解的亚细胞位点和机制。这些研究将使用各种生理，药理，生化，分子和细胞系统进行。最终，在生理和病理生理状态下调节蛋白质代谢的能力需要对蛋白质代谢的途径有详细的机械理解，这是本建议的主题。