Molecular mechanism of ATP-dependent copper transporters

ATP依赖性铜转运蛋白的分子机制

• 批准号: 8490358
• 负责人: SVETLANA LUTSENKO
• 金额: $ 31.87万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8490358
• 关键词: ATP phosphohydrolase; Affect; Bile fluid; Binding; Biochemical; Biological; Biological Assay; Blood; Caco-2 Cells; Cells; Cerebrospinal Fluid; Cisplatin; Code; Confocal Microscopy; Copper; Coupled; Cytosol; Development; Diagnostic; Disease; Electron Transport; Embryo; Enzymes; Equilibrium; Event; Excision; Financial compensation; Genes; Genetic; Goals; Growth and Development function; Hepatolenticular Degeneration; Homeostasis; Human; Hypoxia; In Vitro; Label; Link; Liquid substance; Mediating; Menkes Kinky Hair Syndrome; Metabolic; Metabolism; Metals; Milk; Molecular; Molecular Chaperones; Molecular Conformation; Mutate; Mutation; N-terminal; Organism; Oxidation-Reduction; Pathway interactions; Pharmaceutical Preparations; Phosphorylation; Phosphotransferases; Physiology; Play; Process; Property; Proteins; Regulation; Relative (related person); Reporting; Research; Resistance; Role; Series; Site-Directed Mutagenesis; Solid Neoplasm; System; Testing; Tetanus Helper Peptide; Up-Regulation; Variant; Wilson disease protein; base; cardiogenesis; copper-transporting ATPase; design; disease-causing mutation; hypocupremia; improved; insight; iron metabolism; mutant; overexpression; oxidation; preference; research study; sensor; tool; trafficking

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.

项目概要 该项目的主要目标是了解调节的分子和细胞机制 铜在人体细胞中的运输和分布。铜对于正常生长至关重要 人类有机体的发育。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。门克斯病受影响的基因和 威尔逊氏病分别编码铜转运 ATP 酶 ATP7A 和 ATP7B。这 铜转运 ATP 酶通过将铜输送至人体，在人体铜稳态中发挥核心作用。 铜依赖性酶以及从细胞中输出过量的铜。铜的活性- ATP 酶在分子和细胞水平上受到严格调控。这个的分子机制 人们对监管知之甚少，将在拟议的一系列实验中进行阐明，其中 有四个具体目标。目标 1 将比较铜对 ATP7A 和 ATP7B 的调节 伴侣Atox1。目标 2 将确定氧化/还原对铜 ATP 酶活性的作用。 目标 3 旨在了解激酶介导的磷酸化在调节 Cu- AT酶活性和细胞内定位。目标 4 将描述一系列威尔逊氏病的特征 引起突变来剖析其分子和细胞后果。结果将澄清 每种铜-ATP酶对细胞铜平衡的相对贡献以及生化基础 疾病中一种铜-ATP酶被另一种铜-ATP酶不完全补偿。新的分析工具 将开发细胞中的铜转运蛋白。这项研究的结果将有助于 开发更好的人类铜代谢紊乱的诊断和治疗方法。