Molecular mechanism of ATP-dependent copper transporters

项目摘要 该项目的主要目标是了解调节细胞增殖的分子和细胞机制。 铜在人体细胞中的运输和分布。铜对正常生长至关重要， 人类有机体的发展。铜失衡导致严重的多系统疾病 例如门克斯病和威尔逊病。门克斯病中受影响的基因， Wilson病分别编码铜转运ATP酶ATP 7A和ATP 7 B。的 铜转运ATP酶在人体铜稳态中发挥重要作用， 铜依赖酶以及从细胞中排出过量的铜。铜的活性- ATP酶在分子和细胞水平上受到严格调控。这种现象的分子机制 监管是知之甚少，将阐明在拟议的一系列经验， 有四个具体目标。目的1将比较铜对ATP 7A和ATP 7 B的调节 伴侣蛋白Atox 1.目的2将确定氧化/还原对铜-ATP酶活性的作用。 目的3是为了了解激酶介导的磷酸化在调节铜离子通道中的作用。 ATP酶活性和细胞内定位。目的4将描述一系列威尔逊病 导致突变来分解它们的分子和细胞后果。结果将澄清 每个铜-ATP酶对细胞铜平衡的相对贡献以及生物化学基础 在疾病中，一个铜ATP酶被另一个铜ATP酶不完全补偿。新的分析工具 细胞中铜转运蛋白的研究。这项研究的结果将有助于 开发更好的诊断和治疗人类铜代谢紊乱的方法。

PROJECT SUMMARY 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 experiemnts, 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.