Grant: Project Grant

Many human diseases are caused by aberrant regulation in a class of molecules known as phosphoinositides. These lipid signalling molecules are essential in myriad functions, and are critical in the life and death of every cell in the human body. Disease can be caused by mutations that lead to either increased or decreased phosphoinositide turnover. This proposal focuses on a central phosphatidylinositol 4 kinase enzyme that is required for the growth signalling at the plasma membrane. This proposal focuses on studying the structural and dynamic basis of regulation of PI4K alpha, with a major focus on defining the molecular mechanisms that control how this enzyme is activated and inhibited, and how it can be mis-regulated in human disease. This will be approached using a cutting-edge synergy of state of the art biochemical and biophysical methods including Cryo-Electron Microscopy, and Hydrogen Deuterium Exchange mass spectrometry. A powerful team of collaborators including biophysicists, cell biologists, and chemical biologists has been established to fully apply biophysical discoveries in cellular models of disease. PI4K alpha is an exceptionally important enzyme to understand, as it has been found to be down-regulated in developmental disorders, and up-regulated in human cancer, including high mortality cancers (pancreatic). This proposal focusing on defining the molecular basis of how this enzyme is regulated will reveal novel insight into its role in human disease.