STRUCTURAL STUDIES OF IRON TRANSPORT AND HOMEOSTASIS AND OF ARCHAEAL VIRUSES

Stanford University, Stanford CA

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Abstract

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.