Structure and Function of Copper Trafficking Proteins

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DESCRIPTION (provided by applicant): The broad goal of the research in the area is to develop a complete mechanistic description of the proteins, regulatory processes and mechanisms involved in the intracellular routing of copper. Exciting developments over the past decade have lead to an increase in the understanding of copper homeostasis, its essentiality, toxicity and pivotal role in metabolism. The unique redox properties of copper make it an essential cofactor for a wide range of critical enzymes. Although these enzymes are readily identified (cytochrome c oxidase, superoxide dismutase, dopamine B-hydroxylase etc.) it is still not understood how copper is transported through the body, across membranes, incorporated into enzymes, recycled and excess excreted. Still less is understood about the mechanisms of these processes in normal and diseased states. It is clear that several dysfunctions result from defects in copper metabolism, encountered in some human genetic diseases like Menkes and Wilsons. Utilizing the features of the simple, highly characterized Enteroccus hirae bacterial system, that contributed previously to the understanding of copper metabolism, key mechanistic and regulatory questions will be investigated. The specific aims are: 1) characterize the putative transfer of copper from an import protein to an intracellular transport protein; 2) evaluate the role of the metal ligands in a transport protein to attract and donate copper ions; 3) define, at a molecular level, the metal sensing mechanism of a regulatory molecule. Accomplishment of these goals will further advance the understanding of the mechanisms and the regulation of the copper import and cellular distribution processes.