Mechanistic insights into homeostatic copper acquistion

稳态铜获取的机制见解

• 批准号: 7884615
• 负责人: JAEKWON LEE
• 金额: $ 21.09万
• 依托单位: UNIVERSITY OF NEBRASKA LINCOLN
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7884615
• 关键词: Address; Alzheimer' s Disease; Binding; Biochemistry; Biological Models; Cell Line; Cell membrane; Cells; Cellular biology; Clinical; Coenzymes; Complex; Copper; Coupled; Data; Defect; Degenerative Disorder; Disease; Drug Metabolic Detoxication; Embryonic Development; Employee Strikes; Eukaryota; Event; Family; Family member; Fostering; Free Radicals; Generations; Genetic; Goals; Growth and Development function; Heart failure; Hepatic; Hepatolenticular Degeneration; Hereditary Disease; Homeostasis; Human; In Situ; Integral Membrane Protein; Lead; Link; Mammalian Cell; Mediating; Menkes Kinky Hair Syndrome; Metabolism; Metals; Methionine; Methods; Micronutrients; Mitochondria; Molecular; Molecular Chaperones; Monitor; N-terminal; Neurodegenerative Disorders; Nutritional; Organism; Oxidation-Reduction; Pathology; Pathway interactions; Physiological; Physiological Processes; Physiology; Post-Translational Regulation; Regulation; Research Personnel; Role; Saccharomyces cerevisiae; Signal Transduction; Structure; System; Toxic effect; Yeasts; combat; copper transporter 1; human disease; hypocupremia; insight; iron metabolism; neurotransmission; novel; prevent; protein protein interaction; research study; uptake

DESCRIPTION (provided by applicant): Copper is an essential, yet toxic, micronutrient. Copper serves as a cofactor of enzymes that are vital for normal growth and development. Genetic disorders in copper metabolism, copper-implicated degenerative diseases, and nutritional copper deficiency in various organisms provide striking evidence that homeostatic copper metabolism is an essential physiological process. In the context of these clinical correlations, characterization of the copper transport system represents an important biomedical problem. Ctrl, a highly conserved family of integral membrane protein in eukaryotes, has been identified. While roles of Ctrl in copper metabolism have just begun to be elucidated, the mechanisms of action and regulation of Ctrl which is critical for optimal copper acquisition remain to be determined. Physical and functional interactions between Ctrl and other components involved in copper metabolism are not fully understood. The long-term goals of this proposal are to understand the molecular mechanisms of homeostatic copper transport across the plasma membrane and characterization of the pathways whereby organisms acquire optimal levels of copper. This application focuses on elucidation of the mechanisms of action and regulation of Ctrl copper transporter. Our preliminary data show that the structure, expression levels, subcellular localization and activity of Ctrl are delicately controlled in a copper-dependent manner. Our central hypothesis is that several layers of post-translational regulation of Ctrl maintain optimal cellular copper acquisition. A multi- disciplinary approach combining physiology, biochemistry, cell biology, and genetics will be employed to pursue the following specific aims: 1) We will charaterize molecuar events in the Ctrl multimeric complex that are coupled with copper transport. 2) We will elucidate the roles of the Ctrl amino terminal domain in copper transport. 3) We will define the physiological significance, structural determinants, and signaling involved in copper-induced red ox-sensitive multimerization of Ctrl. Given that Cu acquisition is a central step in Cu metabolism, defining the function, mode of action and regulation of Ctrl could lead to better insights into Cu homeostasis. Considering the fact that Wilson disease, Menkes disease, Alzheimer's disease, and other severe degenerative disorders are linked to defects in copper homeostasis, studies on the molecular mechanisms of copper acquisition would ultimately advance our ability to combat copper-related pathologies.

描述（由申请人提供）：铜是一种必需的，但有毒的微量营养素。铜作为酶的辅助因子，对正常生长和发育至关重要。铜代谢中的遗传性疾病、与铜有关的退行性疾病和各种生物体中的营养性铜缺乏提供了显著的证据，证明稳态铜代谢是一个重要的生理过程。在这些临床相关性的背景下，铜转运系统的表征代表了一个重要的生物医学问题。Ctrl是真核生物中一个高度保守的膜整合蛋白家族。虽然Ctrl在铜代谢中的作用刚刚开始阐明，但Ctrl的作用和调节机制仍有待确定，Ctrl对于最佳铜获得至关重要。Ctrl和参与铜代谢的其他组分之间的物理和功能相互作用尚未完全了解。该提案的长期目标是了解稳态铜跨质膜转运的分子机制和生物体获得最佳铜水平的途径的表征。本申请的重点是阐明Ctrl铜转运蛋白的作用和调节机制。我们的初步数据表明，Ctrl的结构，表达水平，亚细胞定位和活性是微妙的铜依赖性的方式控制。我们的中心假设是，几层的翻译后调控Ctrl保持最佳的细胞铜的收购。本研究将采用生理学、生物化学、细胞生物学和遗传学相结合的多学科方法来实现以下具体目标：1）我们将表征Ctrl多聚体复合物中与铜转运偶联的分子事件。2)我们将阐明Ctrl氨基末端结构域在铜转运中的作用。3)我们将定义铜诱导的红牛敏感性Ctrl多聚化中涉及的生理意义、结构决定因素和信号传导。鉴于铜的获取是铜代谢的中心步骤，定义Ctrl的功能，作用模式和调节可以更好地了解铜的稳态。考虑到威尔逊病、门克斯病、阿尔茨海默病和其他严重退行性疾病与铜稳态缺陷有关的事实，对铜获得的分子机制的研究将最终提高我们对抗铜相关病理的能力。