Molecular mechanism of ATP-dependent copper transporters

ATP依赖性铜转运蛋白的分子机制

• 批准号: 8144880
• 负责人: SVETLANA LUTSENKO
• 金额: $ 33.02万
• 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/8144880
• 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; public health relevance; research study; sensor; tool; trafficking

DESCRIPTION (provided by applicant): 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 experiments, 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. PUBLIC HEALTH RELEVANCE: The project focuses on understanding the function and regulation of human copper transporters ATP7A and ATP7B, associated with Menkes disease and Wilson's disease, respectively. The studies will identify factors that modulate the activity of the copper transporters in cells and characterize the consequences of known disease- causing mutations. The results will contribute to improved diagnostic and treatment of human disorders of copper metabolism.

描述（由申请人提供）：该项目的主要目标是了解调节人类细胞中铜的运输和分布的分子和细胞机制。铜对于人类生物的正常生长和发展至关重要。铜的误水导致严重的多系统疾病，例如Menkes病和威尔逊氏病。分别针对Menkes病和Wilson疾病守则的基因分别针对铜转运ATPASES ATP7A和ATP7B。通过向铜依赖性酶以及从细胞中输出多余的铜来，通过将铜输送到人类铜稳态中，在人类铜稳态中起着核心作用。在分子和细胞水平上严格调节铜的活性。该调节的分子机制知之甚少，并将在提出的一系列实验中阐明，这些实验具有四个特定的目的。 AIM 1将比较铜伴侣ATOX1对ATP7A和ATP7B的调节。 AIM 2将确定铜 - ATPase活性的氧化/还原作用。 AIM 3旨在了解激酶介导的磷酸化在调节Cu-Atpases活性和细胞内定位中的作用。 AIM 4将表征一系列威尔逊疾病，导致突变剖析其分子和细胞后果。结果将阐明每种铜ATPase对细胞铜平衡的相对贡献，以及对一种疾病中一种铜ATPase不完全补偿的生化基础。将开发用于分析细胞中铜转运蛋白的新工具。这项研究的结果将有助于开发更好的诊断和治疗铜代谢的人类疾病。 公共卫生相关性：该项目的重点是理解与Menkes病和Wilson病有关的人类铜转运蛋白ATP7A和ATP7B的功能和调节。 这些研究将确定调节细胞中铜转运蛋白活性的因素，并表征已知疾病引起突变的后果。 结果将有助于改善铜代谢人类疾病的诊断和治疗。