The goals of this project are to understand how the interactions between the transferring receptor (TfR) and transferrin (Tf) and the TfR and the hemochromatosis gene product regulate iron transport into cells. The long term goal of my research is to understand the structure and function of this important receptor. The uptake of iron into mammalian cells involves the binding of Tf to the TfR, followed by internalization of the receptor-Tf complex. Iron uptake is essential for cell division and as a result the TfR has been identified as a proliferation specific marker. It is present on rapidly dividing cells. The uptake of iron into the body and into cells is tightly controlled. Too little iron in mammals results in anemia and failure to thrive. Too much iron results in iron toxicity due to oxidative damage. Hereditary hemochromatosis is a disease of iron overload. Excess iron damages organs and results in liver failure, adult onset diabetes, arthritis and heart failure. It is the most common inherited disease in people of European descent affecting approximately 1 in 400 individuals. Recently the gene was identified and found to bind to the TfR. Key to understanding the regulation of iron uptake is understanding the interactions between the hemochromatosis gene product and between Tf and the TfR. The specific goals of this study application are: to map the interactions between these proteins; to determine how the TfR potentiates the release of iron in the endosome; to determine how the hemochromatosis gene product alters the interaction between Tf and the TfR; and finally to determine the limiting factors in the uptake of iron into cells.

Project Start
2000-05-01
Project End
2001-04-30
Budget Start
1998-10-01
Budget End
1999-09-30
Support Year
2
Fiscal Year
2000
Total Cost
$326,562
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Type
DUNS #
009095365
City
Bronx
State
NY
Country
United States
Zip Code
10461
Ikuta, Katsuya; Yersin, Alexandre; Ikai, Atsushi et al. (2010) Characterization of the interaction between diferric transferrin and transferrin receptor 2 by functional assays and atomic force microscopy. J Mol Biol 397:375-84
Ikuta, Katsuya; Zak, Olga; Aisen, Philip (2004) Recycling, degradation and sensitivity to the synergistic anion of transferrin in the receptor-independent route of iron uptake by human hepatoma (HuH-7) cells. Int J Biochem Cell Biol 36:340-52
Robb, Aeisha; Wessling-Resnick, Marianne (2004) Regulation of transferrin receptor 2 protein levels by transferrin. Blood 104:4294-9
Aisen, Philip (2004) Transferrin receptor 1. Int J Biochem Cell Biol 36:2137-43
Robb, Aeisha D; Ericsson, Maria; Wessling-Resnick, Marianne (2004) Transferrin receptor 2 mediates a biphasic pattern of transferrin uptake associated with ligand delivery to multivesicular bodies. Am J Physiol Cell Physiol 287:C1769-75
Brown, Jing Xu; Buckett, Peter D; Wessling-Resnick, Marianne (2004) Identification of small molecule inhibitors that distinguish between non-transferrin bound iron uptake and transferrin-mediated iron transport. Chem Biol 11:407-16
Navati, Mahantesh S; Samuni, Uri; Aisen, Philip et al. (2003) Binding and release of iron by gel-encapsulated human transferrin: evidence for a conformational search. Proc Natl Acad Sci U S A 100:3832-7
Zak, Olga; Ikuta, Katsuya; Aisen, Philip (2002) The synergistic anion-binding sites of human transferrin: chemical and physiological effects of site-directed mutagenesis. Biochemistry 41:7416-23
Ray, Anandhi; Friedman, Benjamin A; Friedman, Joel M (2002) Trehalose glass-facilitated thermal reduction of metmyoglobin and methemoglobin. J Am Chem Soc 124:7270-1
Han, Okhee; Wessling-Resnick, Marianne (2002) Copper repletion enhances apical iron uptake and transepithelial iron transport by Caco-2 cells. Am J Physiol Gastrointest Liver Physiol 282:G527-33

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