METABOLISM OF PROTEINS

描述(申请人提供)：蛋白质代谢在生理和病理生理状态下被高度调节，如糖尿病、饥饿等。蛋白质在整个生物体内和细胞水平上都是动态存在的，通过蛋白质合成和降解的相对平衡来维持。大部分细胞蛋白质的降解是通过泛素蛋白分解途径进行的，这一途径提供了选择性和特异性。在这里，细胞蛋白通过其内部的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)该途径存在于细胞核内；(2)泛素化是一种新的途径，泛素化以靶蛋白的N端为靶点。我们的总体假设是，细胞蛋白质降解在一定程度上受到其在细胞内的活动位置和不同识别机制的调节。因此，本建议的目的是(1)分析基序，确定泛素连接酶(S)，并确定细胞蛋白质N末端依赖泛素化的生理意义；(2)确定导致几种相互作用的肌肉发育/分化因子降解的亚细胞位置和机制(S)；以及(3)确定糖皮质激素在肌肉加速蛋白质分解代谢中的位置和机制(S)。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，这是本提案的主题。与公共健康相关：蛋白质代谢在健康和疾病状态下都受到高度调控，如糖尿病、饥饿等。如本提案所述，调节这一复杂过程的能力需要详细的机械学理解。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.