The mechanisms through which iron-dependent enzymes receive their metal cofactors are largely unknown. Poly r(C) Binding Protein 1 (PCBP1) is an iron chaperone for ferritin;both PCBP1 and its paralog PCBP2 are required for iron delivery to the prolyl hydroxylase that regulates HIF1. Here we show that PCBP2 is also an iron chaperone for ferritin. Co-expression of PCBP2 and human ferritins in yeast activated the iron deficiency response and increased iron deposition into ferritin. Depletion of PCBP2 in Huh7 cells diminished iron incorporation into ferritin. Both PCBP1 and PCBP2 were co-immunoprecipitated with ferritin in HEK293 cells and expression of both PCBPs was required for ferritin complex formation in cells. PCBP1 and 2 exhibited high-affinity binding to ferritin in vitro. Mammalian genomes encode 4 PCBPs, including the minimally expressed PCBPs 3 and 4. Expression of PCBP3 and 4 in yeast activated the iron deficiency response, but only PCBP3 exhibited strong interactions with ferritin. Expression of PCBP1 and ferritin in an iron sensitive, ccc1 yeast strain intensified the toxic effects of iron, while expression of PCBP4 protected the cells from iron toxicity. Thus, PCBP1 and 2 form a complex for iron delivery to ferritin and all PCBPs may share iron chaperone activity.

Project Start
Project End
Budget Start
Budget End
Support Year
9
Fiscal Year
2013
Total Cost
$1,820,150
Indirect Cost
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State
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Frey, Avery G; Palenchar, Daniel J; Wildemann, Justin D et al. (2016) A Glutaredoxin-BolA Complex Serves as an Iron-Sulfur Cluster Chaperone for the Cytosolic Cluster Assembly Machinery. J Biol Chem :
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Philpott, Caroline C; Ryu, Moon-Suhn (2014) Special delivery: distributing iron in the cytosol of mammalian cells. Front Pharmacol 5:173
Cyert, Martha S; Philpott, Caroline C (2013) Regulation of cation balance in Saccharomyces cerevisiae. Genetics 193:677-713
Leidgens, Sebastien; Bullough, Kimberly Z; Shi, Haifeng et al. (2013) Each member of the poly-r(C)-binding protein 1 (PCBP) family exhibits iron chaperone activity toward ferritin. J Biol Chem 288:17791-802
Philpott, Caroline C (2012) Coming into view: eukaryotic iron chaperones and intracellular iron delivery. J Biol Chem 287:13518-23
Philpott, Caroline C; Leidgens, Sébastien; Frey, Avery G (2012) Metabolic remodeling in iron-deficient fungi. Biochim Biophys Acta 1823:1509-20

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