The Structural Basis for PI(4)P Synthesis

Phosphatidyl inositol phosphates (PIPs) are universal markers of intracellular membranes. PI(4)P is the single most abundant mono phosphoinositide that defines the membranes of the Golgi and TGN. It has been reported to play a key role in membrane biogenesis, vesicular transport, lipid dynamics, and protein and lipid sorting in the TGN. Importantly, the replication of several RNA viruses, mainly the Hepatitis C virus (HCV), depends on PI(4)P. The goal of this project is to get molecular insight in the PI(4)P biosynthesis that takes place at intracellular membranes of all eucaryotic organisms. We will solve the crystal structure of the kinase domain of the PI(4)K and/or the full length enzyme. The structural data will be further analyzed and validated by the means of biochemistry and cell biology. This will improve our understanding of i) the structural architecture of PI(4)Ks ii) explain how specificity is achieved by this enzyme iii) allow the intelligent design of specific inhibitors.