METABOLISM OF PROTEINS

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。最近的证据表明：(1)这一途径存在于细胞核内；(2)泛素化作用以靶蛋白的n端为靶点的新途径。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和不同识别机制的调节。因此，本提案的目的是(1)分析基序，鉴定泛素连接酶，并确定细胞蛋白的n端依赖泛素化的生理意义；(2)确定几个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)确定糖皮质激素在肌肉加速蛋白质分解代谢中的作用部位和机制。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。公共卫生相关性：在健康和疾病状态下，如糖尿病、饥饿等，蛋白质代谢都受到高度调节。调节这一复杂过程的能力需要对本提案中所述的详细的机制理解。我们对蛋白质代谢调节的研究将为治疗策略的发展提供重要的见解。

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.