Molecular mechanism of ATP-dependent copper transporters

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DESCRIPTION (provided by applicant): The major goal of this project is to understand the molecular and cellular mechanisms that regulate the transport and distribution of copper in human cells. Copper is essential for normal growth and development of human organisms. Copper misbalance results in severe multi-system disorders exemplified by Menkes disease and Wilson's disease. The genes affected in Menkes disease and Wilson's disease code for the copper-transporting ATPases ATP7A and ATP7B, respectively. The copper-transporting ATPases play a central role in human copper homeostasis by delivering copper to the copper-dependent enzymes as well as exporting excess copper from cells. The activity of copper- ATPases is tightly regulated at the molecular and cellular level. The molecular mechanism of this regulation is poorly understood and will be elucidated in the proposed series of experiments, which have four specific aims. Aim 1 will compare the regulation of ATP7A and ATP7B by the copper chaperone Atox1. Aim 2 will determine the role of oxidation/reduction for the copper-ATPase activity. Aim 3 is designed to understand the role of a kinase-mediated phosphorylation in modulating the Cu- ATPases activity and intracellular localization. Aim 4 will characterize a series of Wilson's disease causing mutations to dissect their molecular and cellular consequences. The results will clarify the relative contribution of each copper-ATPase to cellular copper balance as well as the biochemical basis for incomplete compensation of one copper-ATPase by the other in disease. New tools for the analysis of copper transporters in cells will be developed. The results of this research will contribute to the development of better diagnostics and treatments for human disorders of copper metabolism. PUBLIC HEALTH RELEVANCE: The project focuses on understanding the function and regulation of human copper transporters ATP7A and ATP7B, associated with Menkes disease and Wilson's disease, respectively. The studies will identify factors that modulate the activity of the copper transporters in cells and characterize the consequences of known disease- causing mutations. The results will contribute to improved diagnostic and treatment of human disorders of copper metabolism.