Investigating the role of UBR4 in proteostasis

The human body is built up from trillions of cells, with these cells forming the various tissues and organs of our bodies. Throughout our life cells perform a huge variety of jobs that allow our bodies to function. Some activities of our cells include ensuring that our DNA is not damaged when a cell divides or repairing damage if it is detected (for instance stopping diseases such as cancer), fighting off infections (cells that eliminate bacteria and viruses), or turning the food we eat into energy (producing the energy molecule called ATP, and other important molecules). Most of these processes performed by the cell require the activity of special types of proteins, called enzymes, that function like small machines. In this project I will focus on a particular family of enzymes that controls the fate of other proteins by tagging them to be removed if they are old or defective. To remove an unwanted protein, this particular type of enzyme will bind to the target protein and attach the tag. Tagged proteins are then recognized by another large enzyme machine where they are disentangled and pulled into a type of barrel. There they are chopped up into small building blocks that are then recycled by the cell. In humans there are over 600 of these tagging enzymes that come in all shapes and sizes. For some of these enzymes we have a good understanding of how they work, but for many we do not. Changes (called mutations) to those enzymes stops them working correctly, and in turn means the cell does not work correctly. These mutant enzymes often cause diseases and thus deeper insight in their functional mechanism is essential. In my research project I will use a special type of microscope that will allow me to determine what some of these enzymes look like, which will help to understand how they work. Besides looking at the enzymes alone, I will also trap them with their protein targets to understand how the process of tagging takes place. These types of studies inform on some of the key processes that allow our cells to maintain themselves, but also informs on the changes that diseases may cause. By understanding the details of how these enzymes bind to and tag their targets, drug molecules can be produced that either block or speed up these processes. In summary the goals of this project are to further our understanding of the fundamental processes of how cells are regulated, which will act as a blueprint for understanding disease and producing new disease treatments.