METABOLISM OF PROTEINS

蛋白质的代谢

• 批准号: 7664965
• 负责人: ALAN L SCHWARTZ
• 金额: $ 33.44万
• 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 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7664965
• 关键词: Biochemical; Catabolism; Cell Nucleus; Cell membrane; Cells; Complex; Cytoplasm; Degradation Pathway; Development; Diabetes Mellitus; Disease; Dissection; Elements; Endocytosis; Endosomes; Equilibrium; Glucocorticoids; Goals; Health; In Vitro; Laboratories; Light; Lysine; Lysosomes; Mediating; Membrane Proteins; Molecular; Muscle; Muscle Development; Myogenin; Nobel Prize; Nuclear; Pathway interactions; Physiological; Process; Protein Biosynthesis; Proteins; Regulation; Regulatory Element; Relative (related person); Role; Series; Site; Specificity; Starvation; Structure; System; Ubiquitin; Ubiquitination; Whole Organism; extracellular; in vivo; insight; multicatalytic endopeptidase complex; novel; protein degradation; protein metabolism; public health relevance; reconstitution; therapeutic development; ubiquitin ligase; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): Protein metabolism 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. Recent evidence demonstrates (1) that this pathway exists within the cell nucleus and (2) a new pathway whereby ubiquitination is targeted to the N-terminus of a target protein. Our overall hypothesis is that cellular protein degradation is regulated in part by its loci of activity within the cell and by distinct recognition mechanisms. The aims of the present proposal are thus (1) to analyze the motif, identify the ubiquitin ligase(s), and determine the physiological significance of N-terminus dependent ubiquitination of cellular proteins; (2) to define the subcellular site and mechanism(s) responsible for degradation of several interacting muscle development/differentiation factors; and (3) to determine the site and mechanism(s) of glucocorticoids in the accelerated protein catabolism in muscle. 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. PUBLIC HEALTH RELEVANCE: Protein metabolism is highly regulated in both health and disease states, such as diabetes, starvation, etc. The ability to modulate this complex process requires a detailed mechanistic understanding as described in this proposal. Our studies on the regulation of protein metabolism will provide significant insights for development of therapeutic strategies.

描述（由申请人提供）：蛋白质代谢在生理和病理生理状态（例如糖尿病，饥饿等）中受到高度调节。无论是在整个生物体内还是在细胞水平上，蛋白质都存在于动态状态下，由蛋白质合成和脱口酸的相对维持。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。最近的证据表明（1）该途径存在于细胞核内，（2）一种新的途径，泛素化针对靶蛋白的N末端。我们的总体假设是细胞蛋白降解部分受细胞内活性基因座和不同识别机制的调节。因此，本建议的目的是（1）分析基序，识别泛素连接酶（S），并确定N端依赖性泛素化细胞蛋白的生理意义； （2）定义负责几种相互作用的肌肉发育/分化因子降解的亚细胞位点和机制； （3）确定肌肉加速蛋白质分解代谢中糖皮质激素的位点和机制。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。公共卫生相关性：蛋白质代谢在健康和疾病状态（例如糖尿病，饥饿等）中受到高度调节。调节这一复杂过程的能力需要本提案中所述的详细机械理解。我们对蛋白质代谢调节的研究将为发展治疗策略的发展提供重要的见解。