Modulation of iron regulatory protein-1 by various metals.
Iron regulatory protein-1 (IRP-1) is known as a cytosolic aconitase and a central regulator of iron (Fe) homeostasis. IRP-1 regulates the expression of Fe metabolism-related proteins by interacting with the Fe-responsive element (IRE) in the untranslated regions of mRNAs of these proteins. However, it is less known whether IRP-1 modulates various non-Fe metals. In the present study, we showed that treatment of homogenously purified IRP-1 with non-Fe metals decreased the affinity to IRE in RNA band shift assays and increased aconitase activity. Non-Fe metals also inhibited (55)Fe incorporation into the fourth labile position of the Fe-S cluster of IRP-1. In PLC hepatoma cells, metal loading inactivated binding activity and activated enzyme activity. It also suppressed transferrin receptor mRNA expression in the cells. These results suggest that various non-Fe metals modulate IRP-1 by conversion of the 3Fe-4S apo-form to a [1 non-Fe metal + 3Fe]-4Fe holo-form.
Oshiro
Satoru
S
Department of Biochemical Genetics, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan. satoru.bgen@mri.tmd.ac.jp
Nozawa
Koji
K
Hori
Makoto
M
Zhang
Chun
C
Hashimoto
Yoshinori
Y
Kitajima
Shigetaka
S
Kawamura
Ken-ichi
K
D000154:Aconitate Hydratase / Q000378:metabolism; D000818:Animals; D001667:Binding, Competitive; D015152:Blotting, Northern; D002104:Cadmium / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000378:metabolism; D002417:Cattle; D002614:Chelating Agents / Q000494:pharmacology; D003300:Copper / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004492:Edetic Acid / Q000494:pharmacology; D006801:Humans; D007501:Iron / Q000378:metabolism*; D035941:Iron Regulatory Protein 1; D035925:Iron-Regulatory Proteins; D007506:Iron-Sulfur Proteins / Q000378:metabolism*; D007700:Kinetics; D008099:Liver / Q000378:metabolism; D008345:Manganese / Q000494:pharmacology; D008628:Mercury / Q000494:pharmacology; D008670:Metals / Q000494:pharmacology*; D009532:Nickel / Q000494:pharmacology; D011485:Protein Binding; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism*; D011990:Receptors, Transferrin / Q000378:metabolism; D014407:Tumor Cells, Cultured
D002614:Chelating Agents; D035925:Iron-Regulatory Proteins; D007506:Iron-Sulfur Proteins; D008670:Metals; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D011990:Receptors, Transferrin; D002104:Cadmium; D008345:Manganese; D003300:Copper; D009532:Nickel; D004492:Edetic Acid; D007501:Iron; D000154:Aconitate Hydratase; D035941:Iron Regulatory Protein 1; D008628:Mercury