STRUCTURAL STUDIES OF IRON TRANSPORT AND HOMEOSTASIS AND OF ARCHAEAL VIRUSES

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 一方面，全世界有10多亿人患有贫血。另一方面，遗传性血色沉着症是已知的最常见的常染色体隐性遗传病，在北欧血统的人中携带率约为1/10。铁超载的许多其他疾病也是已知的，通常会导致50岁前死亡。我们致力于一些与人类铁转运有关的蛋白质的结构研究，包括转铁蛋白受体(TFR)和Steap铁还原酶家族。在另一个不同的脉络，最近的工作也表明，转铁蛋白受体是伽玛酸的靶标，它触发了细胞凋亡。因此，我们也在努力研究TFR与更易溶的藤黄酸类似物的结构。最后，我们还在研究细菌和古生菌的DPSL蛋白，这是铁蛋白超家族中新发现的成员，包含一个定义的硫代铁蛋白基序。这些蛋白质存在于人类最常见的厌氧病原体--脆弱类杆菌和类杆菌中。第二个项目的重点是古生菌病毒的结构研究。已知的感染细菌和真核生物的病毒和噬菌体有5000多种，然而，目前发现的古生菌病毒不到35种，主要是因为人们才刚刚开始寻找它们。第一批嗜热隐翅虫病毒基因组现已完成测序，它们通常与公共数据库缺乏同源性。因此，如果没有直接的生物化学和遗传学研究，就很难为这些病毒基因分配功能。因此，我们从事的是从结构到功能的工作。该项目的重点是两类嗜热隐翅虫病毒。我们现在已经解决了13种隐古病毒蛋白的结构。这些研究正在为生命树上这第三个分支的病毒的生命周期提供一个重要的洞察力，并有望为了解其古细菌宿主的许多基本生化过程提供一个窗口。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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.