1)Hundreds of cellular proteins require iron cofactors for activity, and cells express systems for their assembly and distribution. Molecular details of the cytosolic iron pool used for iron cofactors are lacking, but iron chaperones of the poly(rC)-binding protein (PCBP) family play a key role in ferrous ion distribution. Here we show that, in cells and in vitro, PCBP1 coordinates iron via conserved cysteine and glutamate residues and a molecule of noncovalently bound glutathione (GSH). Proteomics analysis of PCBP1-interacting proteins identified BolA2, which functions, in complex with Glrx3, as a cytosolic 2Fe-2S cluster chaperone. The Fe-GSH-bound form of PCBP1 complexes with cytosolic BolA2 via a bridging Fe ligand. Biochemical analysis of PCBP1 and BolA2, in cells and in vitro, indicates that PCBP1-Fe-GSH-BolA2 serves as an intermediate complex required for the assembly of 2Fe-2S clusters on BolA2-Glrx3, thereby linking the ferrous iron and Fe-S distribution systems in cells. 2) Mammalian cells contain thousands of metalloproteins and have evolved sophisticated systems for ensuring that metal cofactors are correctly assembled and delivered to their proper destinations. Equally critical in this process are the strategies to avoid the insertion of the wrong metal cofactor into apo-proteins and to avoid the damage that redox-active metals can catalyze in the cellular milieu. Iron and zinc are the most abundant metal cofactors in cells and iron cofactors include heme, iron-sulfur clusters, and mono- and dinuclear iron centers. Systems for the intracellular trafficking of iron cofactors are being characterized. This review focuses on the trafficking of ferrous iron cofactors in the cytosol of mammalian cells, a process that involves specialized iron-binding proteins, termed iron chaperones, of the poly rC-binding protein family.

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2019
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Philpott, Caroline C (2018) The flux of iron through ferritin in erythrocyte development. Curr Opin Hematol 25:183-188
Ryu, Moon-Suhn; Duck, Kari A; Philpott, Caroline C (2018) Ferritin iron regulators, PCBP1 and NCOA4, respond to cellular iron status in developing red cells. Blood Cells Mol Dis 69:75-81
Philpott, Caroline C; Ryu, Moon-Suhn; Frey, Avery et al. (2017) Cytosolic iron chaperones: Proteins delivering iron cofactors in the cytosol of mammalian cells. J Biol Chem 292:12764-12771
Ryu, Moon-Suhn; Zhang, Deliang; Protchenko, Olga et al. (2017) PCBP1 and NCOA4 regulate erythroid iron storage and heme biosynthesis. J Clin Invest 127:1786-1797
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 :
Yabe-Wada, Toshiki; Matsuba, Shintaro; Takeda, Kazuya et al. (2016) TLR signals posttranscriptionally regulate the cytokine trafficking mediator sortilin. Sci Rep 6:26566
Li, Fengmin; Bullough, Kimberly Z; Vashisht, Ajay A et al. (2016) Poly(rC)-Binding Protein 2 Regulates Hippo Signaling To Control Growth in Breast Epithelial Cells. Mol Cell Biol 36:2121-31
Philpott, Caroline C; Protchenko, Olga (2016) Fungal physiology: Robbing the bank of haem iron. Nat Microbiol 1:16179
Frey, Avery G; Nandal, Anjali; Park, Jong Hwan et al. (2014) Iron chaperones PCBP1 and PCBP2 mediate the metallation of the dinuclear iron enzyme deoxyhypusine hydroxylase. Proc Natl Acad Sci U S A 111:8031-6
Philpott, Caroline C; Ryu, Moon-Suhn (2014) Special delivery: distributing iron in the cytosol of mammalian cells. Front Pharmacol 5:173

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