Grant: Operating Grant - PA: Institute of Genetics (Bridge Funding)

We are using the model organism Saccharomyces cerevisiae, or baker's yeast, to study a family of enzymes called peptidyl-proline isomerases (PPIs). These enzymes are found in cells from all forms of life, which implies they have very important functions. By working in a model organism that can be genetically manipulated (yeast), we can quickly learn a great deal about the biology of all organisms including man. The function of PPIs is to regulate the activity of protein machines in cells, and they do this by reshaping key functional surfaces of proteins. This reshaping, called proline isomerisation, is best described as a molecular switch that can turn a protein machine on and off -these regulatory events are essential for all biological processes. Budding yeast has thirteen PPI enzymes that flip such 'proline switches' in proteins, but the location of the switches, and the processes they control are not known. We are taking a synergistic genetic and biochemical approach to obtain this information. Our goal is to find these 'proline switches' and understand how they regulate protein function and the flow of information within cells. We have previously demonstrated that proline isomerisation is an important regulatory modification of histone proteins, which package the DNA in our cells. Because genes, the information parcels in our DNA, are controlled at the level of DNA packaging, we have identified a function of PPIs enzymes as gene controllers. We will therefore focus our molecular studies on PPIs that regulate our genes. Importantly, we have recently shown that, like other key factors that control genes, PPIs are mis-regulated in different types of cancer. Thus, learning how peptidyl-proline isomerases function in yeast will also provide insight into how aberrant proline isomerases contribute to human disease.