STRUCTURAL STUDIES OF IRON TRANSPORT AND HOMEOSTASIS AND OF ARCHAEAL VIRUSES

铁运输和体内平衡以及古细菌病毒的结构研究

• 批准号: 8362297
• 负责人: CHARLES MARTIN LAWRENCE
• 金额: $ 0.33万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8362297
• 关键词: Age; Anemia; Apoptosis; Archaeal Viruses; Bacteria; Bacteriophages; Bacteroides fragilis; Bacteroides thetaiotaomicron; Biochemical Genetics; Biochemical Process; Cessation of life; Complex; Databases; Disease; Eukaryota; European; Family; Ferritin; Frequencies; Funding; Grant; Hereditary hemochromatosis; Homeostasis; Human; Iron; Iron Overload; Life; Life Cycle Stages; National Center for Research Resources; Principal Investigator; Proteins; Radiation; Research; Research Infrastructure; Resources; Source; Structure; Transferrin Receptor; Trees; United States National Institutes of Health; Veins; Viral Genes; Viral Genome; Viral Proteins; Virus; Work; analog; cost; gambogic acid; insight; iron (III) reductase; member; pathogen; structural biology

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. On one hand, more than 1 BILLION people world-wide suffer from anemia. On the other, hereditary hemochromatosis is the most prevalent autosomal recessive disease known with a carrier frequency of approximately 1 in 10, in people of northern European extraction. Many other diseases of iron overload are known, often leading to death by age 50. We are engaged in structural studies of a number of proteins involved in human iron transport, including the transferrin receptor (TfR) and the Steap family of ferrireductases. In a different vein, recent work also shows that the transferrin receptor is a target for gambogic acid, which triggers apoptosis. Thus, we are also working towards the structure of TfR in complex with a more soluble gambogic acid analogue. Finally, we are also studying bacterial and archaeal DPSL proteins, a newly identified member of the ferritin superfamily that contain a defining ?thioferritin motif?. These proteins are present in the most common anaerobic human pathogens, Bacteroides fragilis and Bacteroides thetaiotaomicron. A second project focuses on structural studies of Archaeal viruses. More than 5,000 viruses and phage are known that infect bacteria and the eukaryotes, however, less than 35 Archaeal viruses have been identified, primarily because people are just beginning to look for them. The first hyperthermophilic crenarchaeal viral genomes have now been sequenced, and they generally show a lack of homology with the public databases. Thus it is difficult to assign function to these viral genes without direct biochemical and genetic studies. We are thus engaged in a ?function from structure? project that focuses on two families of hyperthermophilic crenarchaeal viruses. We have now solved structures for 13 crenarchaeal viral proteins. These studies are providing a significant insight into the life cycles of viruses from this third branch in the tree of life and are expected to provide a window onto many of the fundamental biochemical processes of their crenarchaeal hosts.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的首席研究员可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 一方面，全世界有超过 10 亿人患有贫血症。另一方面，遗传性血色素沉着病是已知的最常见的常染色体隐性遗传疾病，在北欧血统的人群中，其携带频率约为十分之一。许多其他铁超载疾病是已知的，通常会导致 50 岁之前死亡。我们致力于许多参与人体铁转运的蛋白质的结构研究，包括转铁蛋白受体 (TfR) 和铁还原酶 Steap 家族。另一方面，最近的研究还表明，转铁蛋白受体是藤黄酸的靶标，藤黄酸会引发细胞凋亡。因此，我们还致力于研究 TfR 与更可溶的藤黄酸类似物复合物的结构。最后，我们还在研究细菌和古菌 DPSL 蛋白，这是铁蛋白超家族中新发现的成员，包含定义的“硫代铁蛋白基序”。这些蛋白质存在于最常见的人类厌氧病原体：脆弱拟杆菌和多形拟杆菌中。第二个项目侧重于古菌病毒的结构研究。已知有超过 5,000 种病毒和噬菌体感染细菌和真核生物，但是，已鉴定出的古细菌病毒不到 35 种，这主要是因为人们才刚刚开始寻找它们。第一个超嗜热天穹病毒基因组现已测序，它们通常与公共数据库缺乏同源性。因此，如果没有直接的生化和遗传学研究，很难确定这些病毒基因的功能。因此，我们正在从事“结构的功能”？该项目重点关注两个超嗜热天穹病毒家族。我们现在已经解析了 13 种颅缝病毒蛋白的结构。这些研究为生命树第三个分支的病毒生命周期提供了重要的见解，并有望为了解其穹顶菌宿主的许多基本生化过程提供一个窗口。