Postdoctoral Position Available at the National Institutes of Health
Iron Chaperones and the Distribution of Iron Cofactors within Cells
Posted: April 11, 2017
Postdoctoral position available to study the distribution and utilization of iron cofactors within mammalian cells and tissues. Iron is an essential nutrient for every cell in the human body, yet it can also be a potent cellular toxin. Iron is essential because enzymes that require iron co-factors (namely, heme, iron-sulfur clusters, mononuclear and diiron centers) are involved in virtually every major metabolic process in the cell. Iron deficiency continues to be the most common nutritional deficiency in the world, especially among children and women of childbearing age, where it causes anemia and impairs neurological development and function. Although the pathogenesis of anemia in iron deficiency is well understood, other manifestations of iron deficiency are not understood at the cellular or metabolic level. Iron overload is a feature of an increasing number of human diseases, including genetic disorders such as hereditary hemochromatosis, thalassemias, and Friedreich ataxia, as well as chronic inflammatory diseases of the liver, such as hepatitis C. Hundreds of iron, zinc, copper, and manganese proteins are expressed in human cells, yet little is known about the mechanisms by which these metalloproteins acquire their native metal ligands and avoid mis-metallation. We have made significant advances in understanding the delivery of iron to iron-dependent enzymes in the cytosol.
We identified Poly rC-Binding Protein 1 (PCBP1) as an iron-binding protein that delivers iron to ferritin in human cells (Shi, et al. 2008, Science 320, 1207-10). This was the first description of a cytosolic iron chaperone — a protein that specifically binds iron ions and delivers them to target proteins through direct protein-protein interactions. PCBP1 and its human paralogs are multifunctional adaptor proteins that also bind single-stranded DNA and RNA in a sequence-specific manner to regulate the fate of the nucleic acid. PCBP2, a human paralog of PCBP1, is independently required for the delivery of iron to ferritin. PCBP1 and PCBP2 deliver iron to additional families of target enzymes: the prolyl hydroxylases (PHDs) that regulate the degradation of hypoxia inducible factor 1 (HIF1) and deoxyhypusine hydroxylase (DOHH). Projects currently underway explore the roles of PCBPs in erythroid cell development and the intersection of iron ion chaperones with the Fe-S cluster machinery. Mouse models of PCBP1 and PCBP2 deficiency have been developed and are revealing new functions of these proteins in maintaining iron homeostasis in mammals.
We use the tools of cell biology, genetics and biochemistry to address questions about how cells and animals use iron. The postdoctoral position is fully funded, available immediately, and open to any motivated Ph.D./M.D. with less than five years of postdoctoral experience. NIH is an equal opportunity employer.
Caroline C. Philpott, M. D.
Chief, Genetics and Metabolism Section
Liver Diseases Branch, NIDDK, NIH
Bldg 10, Rm 9B-16
10 Center Drive
Bethesda, MD 20892-1800