Structure and Function of Copper Trafficking Proteins

描述（由申请人提供）：该领域研究的总体目标是对细胞内铜路径中涉及的蛋白质、调节过程和机制进行完整的机制描述。在过去的十年中，令人兴奋的发展导致对铜稳态，其必要性，毒性和代谢中的关键作用的理解增加。铜独特的氧化还原特性使其成为多种关键酶的重要辅助因子。虽然这些酶很容易被识别（细胞色素c氧化酶，超氧化物歧化酶，多巴胺b -羟化酶等），但仍然不清楚铜是如何在体内运输的，穿过膜，结合到酶中，再循环和多余的排泄。对于这些过程在正常和患病状态下的机制，我们了解的还很少。很明显，一些功能障碍是铜代谢缺陷造成的，在一些人类遗传疾病如门克斯和威尔逊中遇到。利用简单、高度表征的hiraenteroccus细菌系统的特点，先前有助于理解铜代谢，关键的机制和调控问题将被研究。具体目的是：1)表征铜从输入蛋白到细胞内转运蛋白的推定转移；2)评估金属配体在运输蛋白中吸引和捐赠铜离子的作用；3)在分子水平上定义调控分子的金属感应机制。这些目标的实现将进一步促进对铜进口和细胞分布过程的机制和调控的理解。

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.