Project 444981

Copper is required for the activity of many enzymes involved in respiration, neuron function, formation of connective tissue, endocrine processes, and radical detoxification in the human body. Wilson disease protein (ATP7B) and structurally similar ATP7A regulate copper concentration in the cell and deliver copper to biosynthetic pathways. These enzymes are targets of many mutations that cause severe metabolic disorders. Importantly, ATP7B and ATP7A are involved in cancer resistance to platinum-based chemotherapeutic drugs. Our research shows that transport of copper and platinum drugs in the cells shares similar mechanism, and copper interaction with ATP7B has many common elements with ATP7B interaction with platinum anticancer drugs. To understand the activity cycle of the copper transporters in healthy cells and under the conditions of chemotherapy with platinum drugs, we will investigate copper and platinum relay from the intracellular metal delivery vehicle ATOX1, through the multiple metal-binding domains of ATP7B, and across the cell membrane. Using nuclear magnetic resonance spectroscopy, biochemical techniques, and methods of cell biology we will investigate the role of copper transport proteins in the intracellular processing and target delivery of the platinum anticancer drugs. This work will help understand the function of an important class of transport proteins, and provide a new insight into the molecular basis of the disorders of copper metabolism. Better understanding of platinum drug transport in the cell will guide design of the novel approaches to overcome certain types of drug resistance in cancer.