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）：在生理和病理生理状态下，如糖尿病、饥饿等，蛋白质的代谢受到高度调节。无论是在整个生物体内还是在细胞水平上，蛋白质都处于动态状态，由蛋白质合成和降解的相对平衡来维持。大部分细胞蛋白质降解是通过泛素蛋白水解途径，它提供了选择性和特异性。在这里，细胞蛋白通过其内部赖氨酸残基被泛素标记，并通过蛋白酶体降解。该通路负责胰岛素依赖型糖尿病骨骼肌蛋白水解的增强，以及胰岛素作用的关键成分IRS-1和IRS-2等许多代谢调节分子的周转。最近的证据表明，这一途径可能存在于细胞核内。我们的总体假设是，细胞蛋白质降解在一定程度上受到细胞内活性位点的调节。此外，最近的数据表明了一种新的蛋白质水解靶向途径，即通过蛋白质的N端进行标记。因此，本提案的目的是(1)分析基序，鉴定组分，并确定细胞蛋白的n端依赖泛素化的生理意义；(2)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、药理学、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途径的详细机制理解，这是本提案的主题。