Ferritin is abundant in specialized cells of iron storage, the hepatocyte and RE cells of adults and embryos and the erythrocytes of embryos (an unusually Mobile storage site). The regulation of red cell ferritin synthesis and the structure of red cell ferritin related to function was investigated. Regulation: Iron increased the use of preformed ferritin mRNA; high concentration and saturation of transferrin coincided with erythrocyte iron storage; a histone 2A subtype was correlated with inducible ferritin synthesis being present in mature embryonic cells, immature embryonic and adult cells, and absent in adult erythrocytes. Structure: An Fe2+ - Fe3+ binding site on apoferritin was demonstrated which affected iron deposition; phosphorylation of red cell ferritin-specific serine was demonstrated which increased iron release in vitro. The results are compatible with two hypothesis: (1) regulation of red cell ferritin synthesis in adults and embryos depends both on the extracellular environment (transferrin concentration and saturation) and the intracellular environment (storage of ferritin mRNA, histone 2A variants); (2) cell-specific differences in the protein shell of ferritin, altered by phosphorylation e.g., affect availability of stored iron in vivo, thereby explaining the use of the red cell as a storage site in embryos when the iron demand is high. The two hypotheses will be tested by investigating, in relation to iron storage, Regulation: (1) translational control of ferritin synthesis by iron; (2) changes in histone 2A structure; change of concentration in ferritin gene transcripts of adult and embryonic red cells and mutant and normal murine cells; (3) transferrin binding by adult and embryonic red cells; Structure: (4) red cell ferritin phosphorylation in vitro and in vivo; (5) the Fe-apoferritin binding site in modified ferritin, during oxidation of Fe2+, influenced by Pi. The results will be important for understanding general mechanisms of cell development, translational control of protein synthesis and iron protein interactions and specific knowledge of normal and abnormal (e.g. thalassemic) erythropoiesis and iron metabolism.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Method to Extend Research in Time (MERIT) Award (R37)
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Hematology Subcommittee 2 (HEM)
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North Carolina State University Raleigh
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United States
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Theil, Elizabeth C; Turano, Paola; Ghini, Veronica et al. (2014) Coordinating subdomains of ferritin protein cages with catalysis and biomineralization viewed from the C4 cage axes. J Biol Inorg Chem 19:615-22
Khan, Mateen A; Ma, Jia; Walden, William E et al. (2014) Rapid kinetics of iron responsive element (IRE) RNA/iron regulatory protein 1 and IRE-RNA/eIF4F complexes respond differently to metal ions. Nucleic Acids Res 42:6567-77
Behera, Rabindra K; Theil, Elizabeth C (2014) Moving Fe2+ from ferritin ion channels to catalytic OH centers depends on conserved protein cage carboxylates. Proc Natl Acad Sci U S A 111:7925-30
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Tosha, Takehiko; Behera, Rabindra K; Theil, Elizabeth C (2012) Ferritin ion channel disorder inhibits Fe(II)/O2 reactivity at distant sites. Inorg Chem 51:11406-11
Bertini, Ivano; Lalli, Daniela; Mangani, Stefano et al. (2012) Structural insights into the ferroxidase site of ferritins from higher eukaryotes. J Am Chem Soc 134:6169-76
Theil, Elizabeth C; Chen, Huijun; Miranda, Constanza et al. (2012) Absorption of iron from ferritin is independent of heme iron and ferrous salts in women and rat intestinal segments. J Nutr 142:478-83
Tosha, Takehiko; Behera, Rabindra K; Ng, Ho-Leung et al. (2012) Ferritin protein nanocage ion channels: gating by N-terminal extensions. J Biol Chem 287:13016-25
Ma, Jia; Haldar, Suranjana; Khan, Mateen A et al. (2012) Fe2+ binds iron responsive element-RNA, selectively changing protein-binding affinities and regulating mRNA repression and activation. Proc Natl Acad Sci U S A 109:8417-22
Theil, Elizabeth C (2011) Iron homeostasis and nutritional iron deficiency. J Nutr 141:724S-728S

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