Grant: Operating Grant

The machinery used by the cell to perform essential biological processes is made up of large molecular assemblies. These assemblies are effectively miniature machines that are composed of moving parts. Understanding how these machines function requires a detailed study of their three-dimensional structures and how these structures change over time as the machines carry out their tasks in the cell. One such large system is the proteasome, the central molecular machine for removal of damaged and misfolded proteins from the cell. This complex plays a critical role in the degradation of proteins that regulate crucial cellular processes such as cell division, gene expression, signal transduction and cell death. The importance of this system is underscored by the fact that it is a target for anti-cancer and anti-inflammatory drugs. Here we will use nuclear magnetic resonance (NMR) spectroscopy approaches that we have developed to study the proteasome and its interactions with targets that regulate its function. We will also study interactions between the proteasome and the protein molecules that it degrades. Additionally, new NMR methods will be advanced, as required. A detailed description of how the proteasome and its partners interact will be obtained, providing a basis for the rational design of novel therapeutics to be used in the fight against classes of cancers and neurodegenerative diseases.