Structural basis of human TRIAP1/PRELI function in mitochondrial lipid transport and apoptosis

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Mitochondria are the power generator for a cell as they are able to convert energy into usable forms. They also play important roles in the orchestrating cell growth and as well as programmed cell death. Diseases such as cancer arise when a series of unwelcome changes occur in some of these cellular processes, causing the cell to multiply out of control. Before we can identify what goes wrong in cancers it is necessary to understand exactly how our cells normally work. Mitochondrial function requires a highly coordinated supply of proteins and fat-like molecules called phospholipids. In humans two families of proteins, called TRIAP1 and PRELI, play a key role in maintaining the lipid balance in mitochondria. They interaction together in a tight complex, which promotes the transfer of important lipid precurcers from the outer mitochondrial membrane to the inner. TRIAP1/PRELI also play a role in preventing cells from entering into programmed cell death (known as apoptosis) when the cell is under stress. For example, women with breast cancer who produce a lot of TRIAP1 respond poorly to chemotherapy by virtue of their cancer cell being protected from the drug-induce death. In this proposal, we will propose to study at the atomic level how TRIAP1/PRELI perform these functions. By using nuclear magnetic resonance (NMR) and X-ray diffraction methods, the shape and flexibility of relevant protein complexes will be imaged in solution. Insight from these structural studies will shed light on the mechanisms that underlie fundamental aspects of cellular regulation. In turn, this would lead to a better understanding of how the body responds to drug treatments in cancer and may lead to new treatments ways of monitoring the progress of current treatments.