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

点击翻译按钮获取中文摘要

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.