Molecular mechanism of ATP-dependent copper transporters

项目总结 这个项目的主要目标是了解调节细胞周期的分子和细胞机制。 铜在人体细胞中的运输和分布。铜对正常生长和 人类有机体的发展。铜失衡导致严重的多系统紊乱 以门克斯病和威尔逊病为例。影响门克斯病的基因和 分别为铜转运酶ATP7A和ATP7B的威尔逊病编码。这个 铜转运ATPase在人类铜稳态中发挥着核心作用，它将铜输送到 铜依赖的酶以及从细胞中输出过多的铜。铜的活动性- ATPase在分子和细胞水平上受到严格的调控。这种现象的分子机制 人们对监管知之甚少，并将在拟议的一系列经验中加以阐明，这些经验 有四个具体目标。目的1比较铜对ATP7A和ATP7B的调节作用 伴侣Atox1。目标2将确定氧化/还原对铜-ATPase活性的作用。 AIM 3旨在了解激酶介导的磷酸化在调节铜离子的作用。 ATPase活性和细胞内定位。Aim 4将描述一系列肝豆状核变性 导致突变剖析其分子和细胞后果。结果将澄清 各铜-ATPase对细胞铜平衡的相对贡献及其生化基础 在疾病中，一种铜-ATPase被另一种酶不完全代偿。用于分析的新工具 将开发细胞内铜转运蛋白的新技术。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.