Iron-responsive element binding protein

Synthesis of the transferrin receptor (TfR) and that of ferritin are reciprocally linked to cellular iron content. Specific untranslated sequences of the mRNAs for both proteins (named iron response elements) interact with a cytosolic protein sensitive to variations in levels of cellular iron (iron-responsive element-binding protein). When iron levels are high, cells use stored ferritin mRNA to synthesize ferritin, and the TfR mRNA is degraded. In contrast, when iron levels are low, the TfR mRNA is stabilized and increased synthesis of receptors occurs, while ferritin mRNA is apparently stored in an inactive form. This is an important example of control of expression of proteins at the translational level. 

Kennedy, M.C., Mende-Mueller, L., Blondin, G.A., and Beinert, H. 1992. Purification and characterization of cytosolic aconitase from beef hver and its relationship to the iron-responsive element binding protein. Proceedings of the National Academy of Sciences of the USA 89 11730-11734. 

Abbreviations NMDA N-methyl-D-aspartate GAPDH glycerine aldehyde-3-phosphate dehydrogenase IRE-BP iron responsive element binding protein OMDM transferase O -methylguanine-DNA methyltransferase... 

Aconitase exists as both mitochondrial and cytosolic isoenzyme forms of similar structure. However, the cytosolic isoenzyme has a second function. In its apoenzyme form, which lacks the iron-sulfur cluster, it acts as the much-studied iron regulatory factor, or iron-responsive element binding protein (IRE-BP). This protein binds to a specific stem-loop structure in the messenger RNA for proteins involved in iron transport and storage (Chapter 28).86/9°... 

Hail DJ, Rouaoult TA, Harford JB, Kennedy MC, Bondin GA, Beinert H, Klausner RD (1992) Cellular regulation of the iron-responsive element binding protein disassembly of the cubane iron-sulfur cluster results in high-affinity RNA binding. Proc Natl Acad Sci USA 89 11735-11739... 

Guo B, Yu Y, Leibold EA (1994) Iron regulates cytoplasmic levels of a novel iron-responsive element-binding protein without aconitase activity. J Biol Chem 269 24252-24260... 

Control of intracellular iron concentrations by the iron-response element-binding protein (IRE-BP) is an elegant example of a single protein that regulates the translation of one mRNA and the degradation of another. When intracellular iron stores are low, this dual control system operates to increase the level of free Iron Ions available for Iron-requiring enzymes when Iron Is In excess, the system operates to prevent accumulation of toxic levels of free Ions. It Is one of the simplest and best-understood examples of protein-mediated translational control. 

Jaffrey, S. R., Cohen, N. A., Rouault, T. A., Klausner, R. D., and Snyder, S. H. (1994). The iron-responsive element binding protein A novel target for synaptic actions of nitric oxide. Proc. Natl. Acad. Sci. U.S.A. 91, 12994-12998. 

Fig. 16.23. Translational regulation of ferritin synthesis. The mRNA for ferritin has an iron response element (IRE). When the iron response element binding protein, IRE-BP does not contain bound iron, it binds to IRE, preventing translation. When IRE-BP binds iron, it dissociates, and the mRNA is translated.

Fig. 16.24. Regulation of degradation of the mRNA for the transferrin receptor. Degradation of the mRNA is prevented by binding of the iron response element binding protein (IRE-BP) to iron response elements (IRE), which are hairpin loops located at the 3 -end of the transferrin receptor mRNA. When iron levels are high, IRE-BP binds iron and is not bound to the mRNA. The mRNA is rapidly degraded, preventing synthesis of the transferrin receptor.

Regulation of transcription by iron. A cell s ability to acquire and store iron is a carefully controlled process. Iron obtained from the diet is absorbed in the intestine and released into the circulation, where it is bound by transferrin, the iron transport protein in plasma. When a cell requires iron, the plasma iron-transferrin complex binds to the transferrin receptor in the cell membrane and is internalized into the cell. Once the iron is freed from transferrin, it then binds to ferritin, which is the cellular storage protein for iron. Ferritin has the capacity to store up to 4,000 molecules of iron per ferritin molecule. Both transcriptional and translational controls work to maintain intracellular levels of iron (see Figs. 16.23 and 16.24). When iron levels are low, the iron response element binding protein (IRE-BP) binds to specific looped structures on both the ferritin and transferrin receptor mRNAs. This binding event stabilizes the transferrin receptor mRNA so that it can be translated and the number of transferrin receptors in the cell membrane increased. Consequently, cells will take up more iron, even when plasma transferrin/iron levels are low. The binding of IRE-BP to the ferritin mRNA, however, blocks translation of the mRNA. With low levels of intracellular iron, there is little iron to store and less need for intracellular ferritin. Thus, the IRE-BP can stabilize one mRNA, and block translation from a different mRNA. 

Z Ornithine carbamyl transferase, iron responsive element binding protein... 

Rouault TA, Haile DJ et al (1992) An iron-sulfur cluster plays a novel regulatory role in the iron-responsive element binding protein. Biometals 5 131-140... 

NO produced by the cells upon cytokine induction, or added as a gas to the recombinant protein, converts the iron-regulatory protein (also called iron-regulatory factor [IRF] or iron-responsive element-binding protein [IRE-BP]) to the same condition as low iron, causing a binding of the protein to mRNA (Drapier et al. 1993, Weiss et al. 1993). 

Leibold EA, Guo B (1992) Iron-dependent regulation of ferritin and transferrin receptor expression by the iron-responsive element binding protein. Annu Rev Nutr 12 345-368... 

Basilion JP, Rouault TA, Massinople CM, Klausner RD, Burgess WH. The iron-responsive element-binding protein localization of the RNA-binding site to the aconitase active-site cleft. Proc Natl Acad Sci USA 1994 91 574-578. 

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