Molecular biology of ATM1, a putative mitochondrial iron transporter

ATM1（一种假定的线粒体铁转运蛋白）的分子生物学

• 批准号: 6484165
• 负责人: David M Koeller
• 金额: $ 23.1万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-05-01 至 2002-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6484165
• 关键词: Saccharomyces cerevisiae; biochemical evolution; enzyme deficiency; free radical oxygen; gene expression; heme; human genetic material tag; inborn metal metabolism disorder; iron metabolism; membrane transport proteins; mental retardation; mitochondria; molecular pathology; protein protein interaction; protein structure function; sideroblastic anemia; tissue /cell culture

The focus of this project is primarily the function of the yeast mitochondrial ABC transporter encoded by the ATM1 gene. Prior research has demonstrated a role for the TM1 protein in mitochondrial iron homeostasis. Our current hypothesis is that the ATM1 protein is a mitochondrial iron exporter. Deletion of the ATM1 gene in yeast results in mitochondrial iron overload. Associated with the mitochondrial iron accumulation resulting from an ATM1 mutation is a loss of mitochondrial respiratory function and accumulation of mitochondrial DNA mutations. These phenomena are presumed to occur as a result of an increased rate of formation of oxygen radicals catalyzed by the accumulated iron. A human homolog of the yeast ATM1 protein is encoded by the ABC7 gene. We recently identified an inherited mutation in the ABC7 gene as the cause of X-linked sideroblastic anemia and ataxia. Symptoms of male patients affected with this X-linked disorder include a congenital ataxia resulting from a developmental defect in the cerebellum. Patients also have a chronic sideroblastic anemia, which is characterized by the accumulation of iron in the mitochondria of erythroid precursor cells in the bone marrow. The yeast Saccharomyces cerevisiae has been shown to be an excellent model system for the study of mammalian copper and iron metabolism. Many of the yeast proteins which function in cellular iron and copper homeostasis have human homologs which have been implicated in inherited disease. We have shown that the human ABC7 protein is capable of complementing a yeast ATM1 deletion, indicating that the two proteins perform similar functions in the mitochondria. The specific aims of this proposal are; 1) To study the regulation of ATM1 expression and function by heme. 2) To perform a structure-function analysis of the ATM1 homolog of the yeast ATM1 protein. The long term goal of this research is an increased understanding of mitochondrial iron homeostasis, and the role of dysfunction in this process in human disease.

该项目的重点主要是由ATM1基因编码的酵母线粒体ABC转运蛋白的功能。先前的研究表明，TM1蛋白在线粒体铁稳态中的作用。我们目前的假设是ATM1蛋白是线粒体铁的出口商。酵母中ATM1基因的缺失导致线粒体铁超载。与ATM1突变产生的线粒体铁积累相关的是线粒体呼吸功能的丧失和线粒体DNA突变的积累。这些现象被认为是由于累积铁催化的氧自由基的形成速率增加而发生的。酵母ATM1蛋白的人类同源物由ABC7基因编码。我们最近将ABC7基因中的遗传突变确定为X连锁的Sideroblastic贫血和共济失调的原因。患有这种X连锁疾病的男性患者的症状包括小脑发育缺陷引起的先天性共济失调。患者还患有慢性铁细胞性贫血，其特征是铁在骨髓中线粒体的线粒体中积累。酿酒酵母的酵母菌已被证明是研究哺乳动物铜和铁代谢的出色模型系统。许多在细胞铁和铜稳态中起作用的酵母蛋白都有与遗传疾病有关的人类同源物。我们已经表明，人ABC7蛋白能够补充酵母ATM1缺失，表明这两种蛋白在线粒体中执行相似的功能。该提案的具体目的是： 1）研究血红素对ATM1表达和功能的调节。 2）对酵母ATM1蛋白的ATM1同源物进行结构功能分析。这项研究的长期目标是对线粒体铁稳态的了解越来越多，以及功能障碍在此过程中的作用在人类疾病中。