Structure and Function of Copper Trafficking Proteins

描述（由申请人提供）：该领域研究的广泛目标是开发一个完整的机制描述的蛋白质，调节过程和机制参与细胞内的铜路由。在过去的十年中，令人兴奋的发展导致了对铜稳态，其重要性，毒性和代谢中的关键作用的理解增加。铜的独特氧化还原性质使其成为广泛的关键酶的重要辅因子。虽然这些酶很容易识别（细胞色素c氧化酶，超氧化物歧化酶，多巴胺B-羟化酶等）。目前还不清楚铜是如何通过身体、跨膜、进入酶、再循环和过量排泄的。关于这些过程在正常和疾病状态下的机制仍然知之甚少。很明显，一些功能障碍是由于铜代谢缺陷引起的，在一些人类遗传疾病中遇到，如门克斯和威尔逊。利用简单的，高度特征化的肠球菌细菌系统的功能，有助于以前的铜代谢的理解，关键的机制和监管问题将进行调查。具体目标是：1）表征铜从输入蛋白到细胞内转运蛋白的假定转移; 2）评估转运蛋白中金属配体吸引和供给铜离子的作用; 3）在分子水平上定义调节分子的金属传感机制。这些目标的实现将进一步推进对铜输入和细胞分布过程的机制和调节的理解。

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.