Iron responsive elements

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. 

Figure 18.14 Evidence for an iron-responsive element in the 5 -UTR of APP mRNA. APP 5 -UTR sequences were computer-folded to generate the predicted RNA stem. (From Rogers et al., 2002. Reproduced by permission of the Journal of Biological Chemistry.)...

Rogers, J.T., Randall, J.D., Cahill, C.M., Eder, P.S., et al. (2002) An iron-responsive element type II in the 5 -untranslated region of the Alzheimer s amyloid precursor protein transcript, J. Biol. Chem., 277, 45518-45528. 

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... 

The iron responsive element, a critical factor in the control of proteins involved in iron utilization, has been identified as the cytoplasmic form of the iron-sulfur protein aconitase (Kennedy et al., 1992). Activated macrophages have been shown to activate this element, presumably by attack of the iron-sulfur cluster by NO (Drapier et al., 1993). It has been claimed that this attack is mediated by peroxynitrite (Castro et al., 1994 Hausladen and Fridovich, 1994, but this conclusion is not universally accepted. 

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°... 

SELEX has also allowed the characterization of the RNA hairpin, which constitutes the iron responsive element (IRE) recognized by the iron regulatory factor (IRF) protein to post-transcriptionally regulate translatability and decay of mRNAs involved in iron import and storage in eukaryotic cells (Henderson et al., 1994). 

Henderson, B.R., Menotti, E., Bonnard, C. and Kuhn, L.C. (1994) Optimal sequence and structure of iron-responsive elements. Selection of RNA stem-loops with high affinity for iron regulatory factor. J. Biol. Chem., 269, 17481-17489. 

This simple RNA stemloop serves as an illustration of how both steady-state and time-resolved fluorescence together provide a detailed description of the properties of an RNA (Hall and Williams, 2004). The sequence of the iron response element (IRE) RNA hairpin loop [C6A7G8U9G10C11] is phylogenetically conserved (numbered from our construct). Cytidine 6 and... 

Laing, L. G., and Hall, K. B. (1996). A model of the iron responsive element RNA hairpin loop structure determined from NMR and thermodynamic data. Biochemistry 35, 13586-13594. 

McCallum, S. A., and Pardi, A. (2003). Refined solution structure of the iron-responsive element RNA using residual dipolar couplings. J. Mol. Biol. 326, 1037—1050. 

Iron regulatory proteins (IRPs) regulate the cellular iron level in mammalian cells. IRPs are known as cytosol mRNA binding proteins which control the stability or the translation rate of mRNAs of iron metabolism-related proteins such as TfR, ferritin, and 5-aminolevulinic acid synthetase in response to the availability of cellular iron [19-21] after uptake [5]. The regulatory mechanism involves the interaction between the iron-responsive element (IRE) in the 3 or 5 untranslated regions of the transcripts and cytosolic IRPs (IRP-1 and -2). IRP-1 is an iron-sulfur (Fe-S) protein with aconitase activity containing a cubane 4Fe-4S cluster. When Fe is replete, IRP-1 prevails in a 4Fe-4S form as a holo-form and is an active cytoplasmic aconitase. As shown in Fig. 3, when Fe is deplete, it readily loses one Fe from the fourth labile Fe in the Fe-S cluster to become a 3Fe-4S cluster and in this state has little enzymatic activity [22, 23]. 

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... 

---