Structure and Function of Iron Regulatory Proteins

铁调节蛋白的结构和功能

• 批准号: 7209662
• 负责人: KARL W VOLZ
• 金额: $ 29.83万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-30 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7209662
• 关键词: Aconitate Hydratase; Affinity; Amino Acids; Aminolevulinate; Anemia; Animals; Be++ element; Beryllium; Binding; Biochemical; Biochemical Reaction; Biological; Biological Assay; Blindness; Cardiac cirrhosis; Catalysis; Cells; Chemistry; Cirrhosis; Citric Acid Cycle; Complex; Complication; Crystallography; Diet; Disease; Elements; Environment; Enzymes; Failure; Ferritin; Gene Expression Regulation; H ferritin; Heart Diseases; Heme; Hemochromatosis; Homeostasis; Human; Impairment; In Vitro; Indium; Inherited; Iron; Iron Overload; Iron deficiency anemia; Iron-Regulatory Proteins; Knowledge; L-ferritin; Lead; Life; Ligand Binding; Ligase; Malignant Neoplasms; Metabolic; Methods; Modeling; Molecular; Molecular Biology; Molecular Genetics; Nature; Numbers; Nutritional; Organism; Outcome; Oxidation-Reduction; Point Mutation; Proteins; RNA; RNA Binding; Range; Regulation; Research Personnel; Role; Site; Specificity; Structure; Sum; System; Testing; Transferrin Receptor; Transition Elements; Variant; aqueous; base; combinatorial; human WNT2 protein; in vivo; iron metabolism; mutant; nervous system disorder; novel; programs; research study; stem; structural biology; therapeutic target; uptake

DESCRIPTION (provided by applicant): Practically all life forms require iron. Most iron in the environment is oxidized and virtually insoluble. A further complication is that iron's aqueous chemistry can generate highly toxic oxidizing species. Hence organisms must tightly regulate both the quantity and the state of iron in the cell. In humans, the failure to acquire adequate iron from the diet results in iron deficiency anemia, a major nutritional problem worldwide. In addition, imbalances in iron metabolism such as hereditary hyperferritinemia and hemochromatosis can lead to a number of diseases in humans, including blindness, cirrhosis, cardiac disease, neurological disorders, and cancer. Iron transport, utilization, and storage in animal cells is regulated post-transcriptionally by two iron regulatory proteins, IRP1 and IRP2. The IRPs reversibly bind to highly conserved stem-loop structures known as iron responsive elements (IREs) in the mRNAs encoding the iron transport and storage proteins, thereby providing coordinated, reciprocal iron regulation. The IRPs are themselves regulated by the cellular iron status, where high intracellular iron concentrations suppress their IRE binding activities. High iron levels convert IRP1 into a cytosolic aconitase enzyme, complete with an Fe-S cluster. Thus IRP1 is bifunctional, and the interconversion between its two forms underlies its regulation of gene expression. The IRP: IRE system is one of the best-understood post-transcriptional mechanisms of regulation, but until now, no structural information was available. We have recently determined the structure of three IRP1: IRE complexes. Using those results, we have developed a model to explain IRPI's selectivity in multiple-IRE recognition, and we have also proposed a model for the switch mechanism that regulates IRP1 interconversion. To test these hypotheses, and to complete the long-term objective of explaining the molecular details of control by this key metabolic regulator, we will 1) Determine the structural basis for IRE recognition and differential regulation by IRP1; and 2) Determine the nature of the switch mechanism in IRP1. These experiments will be performed using the methods of molecular biology and x-ray crystallography. The results will potentially generate novel targets for therapeutic approaches to diseases of iron metabolism.

描述（由申请人提供）：几乎所有生命形式都需要铁。环境中的大多数铁都被氧化并且几乎不溶。更复杂的是，铁的水溶液化学会产生剧毒的氧化物质。因此，生物体必须严格调节细胞中铁的数量和状态。对于人类来说，未能从饮食中获取足够的铁会导致缺铁性贫血，这是世界范围内的一个主要营养问题。此外，铁代谢失衡，如遗传性高铁蛋白血症和血色素沉着症，可导致人类多种疾病，包括失明、肝硬化、心脏病、神经系统疾病和癌症。动物细胞中铁的运输、利用和储存受到两种铁调节蛋白 IRP1 和 IRP2 的转录后调节。 IRP 可逆地与编码铁转运和储存蛋白的 mRNA 中被称为铁反应元件 (IRE) 的高度保守的茎环结构结合，从而提供协调的、相互的铁调节。 IRP 本身受细胞内铁状态的调节，细胞内高铁浓度会抑制其 IRE 结合活性。高铁水平将 IRP1 转化为胞质乌头酸酶，并带有 Fe-S 簇。因此，IRP1 具有双功能，其两种形式之间的相互转换是其基因表达调节的基础。 IRP：IRE系统是最容易理解的转录后调节机制之一，但到目前为止，还没有结构信息可用。我们最近确定了三个 IRP1: IRE 复合物的结构。利用这些结果，我们开发了一个模型来解释 IRPI 在多重 IRE 识别中的选择性，并且我们还提出了一个调节 IRP1 相互转换的开关机制的模型。为了检验这些假设，并完成解释这一关键代谢调节因子控制的分子细节的长期目标，我们将 1) 确定 IRE 识别和 IRP1 差异调节的结构基础； 2) 确定IRP1 中切换机制的性质。这些实验将使用分子生物学和 X 射线晶体学方法进行。这些结果可能会为铁代谢疾病的治疗方法产生新的靶标。