Iron-responsive element binding protein IRE-BP

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°... 

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. 

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. 

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). 

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... 

Consider ferritin first. Ferritin mRNA includes a stem-loop structure termed an iron-response element (IRE) in its 5 untranslated region (Figure 31.38). This stem-loop binds a 90-kd protein, czAlsd m IRE-bindingprotein (IRE-BP), that blocks the initiation of translation. When the iron level increases, the IRE-BP binds iron as a 4Fe-4S cluster. The IRE-BP bound to iron cannot bind RNA, because the binding sites for iron and RNA substantially overlap. Thus, in the presence of iron, ferritin mRNA is released from the IRE-BP and translated to produce ferritin, which sequesters the excess iron. 

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