Characterisation of putative targets of the ubiquitin-protein ligase, Nedd4

细胞蛋白质的合成和降解取决于细胞的代谢状态。许多细胞蛋白质的正常周转是由一种称为泛素的高度保守的多肽参与的复杂途径所介导的。依赖泛素的蛋白质分解对于维持细胞的健康至关重要。许多细胞周期蛋白、膜通道、受体和某些癌基因产物是泛素依赖的转运的已知靶点。显然，这种严密调控的蛋白质下调机制的缺陷可能会导致一种病理状态，因此在分子水平上了解这一途径是如何调控的是重要的。在多步泛素途径中，需要一些称为E3的组成酶来指定要降解的靶标。我们发现了一种这样的酶Nedd4。受Nedd4调控的蛋白质之一是上皮钠通道(ENaC)。Nedd4介导的ENaC调节缺失导致利德尔综合征，这是高血压的一种遗传形式。由于Nedd4在许多组织和发育过程中都有表达，我们预测Nedd4可能除了调节ENaC外，还调节其他重要的蛋白质。我们最近发现了几种与Nedd4相互作用的蛋白质。其中一些蛋白质可能在细胞调节和发育过程中发挥重要作用。拟议的项目旨在对这些蛋白质进行表征。我们相信，通过对这些蛋白质的研究，我们将对细胞调控途径有更多的了解。总之，Nedd4是一种参与细胞调控的重要蛋白质，在人类疾病中具有已被证实的作用。研究Nedd4的特征靶点对于理解细胞调控的分子基础及其在疾病中的意义至关重要。

Cellular proteins are synthesised and degraded depending on the metabolic state of the cell. The normal turnover of a number of cellular proteins is mediated by a complex pathway involving a highly conserved polypeptide called ubiquitin. Ubiquitin-dependent proteolysis of a number of proteins is essential for the maintenance of the health of a cell. Many cell cycle proteins, membrane channels, receptors and products of some oncogenes are known targets of the ubiquitin-dependent turnover. Clearly, a defect in this tightly regulated mechanism for the downregulation of proteins can result in a pathological condition and therefore it is important to understand how this pathway is regulated at molecular level. In the multistep ubiquitin pathway, some component enzymes called E3 are required for specifying the targets to be degraded. We discovered one such enzyme Nedd4. One of the proteins regulated by Nedd4 is epithelial sodium channel (ENaC). Loss of Nedd4-mediated regulation of ENaC results in Liddle's Syndrome, a genetic form of hypertension. Since Nedd4 is expressed in many tissues and during development, we predicted that Nedd4 may regulate other important proteins in addition to ENaC. We have recently identified several proteins which interact with Nedd4. Some of these proteins are likely to play important roles in cellular regulation and during development. The proposed project is designed to characterise these proteins. We believe that by studying these proteins we will learn a great deal about the cellular regulatory pathways. In summary, Nedd4 is an important protein involved in cellular regulation and has a proven role in human disease. A study of characterising targets of Nedd4 will be vital in understanding the molecular basis of cell regulation and its implication in disease.