IRE-binding protein

IRPl can become an IRE-binding protein in the absence of an intact iron-sulfur cluster is a reminder that apoproteins can change conformationally and acquire new functions. 

Figure 31.39. Transferrin-receptor mRNA. This mRNA has a set of ironresponse elements (IREs) in its 3 untranslated region. The binding of the IRE-binding protein to these elements stabilizes the mRNA but does not interfere with translation.

In eukaryotes, genes encoding proteins that transport and store iron are regulated at the translational level. Iron-response elements, structures that are present in certain mRNAs, are bound by an IRE-binding protein when this protein is not binding iron. Whether the expression of a gene is stimulated or inhibited in response to changes in the iron status of a cell depends on the location of the IRE within the mRNA. 

The IRE-binding activity was first monitored in rat cytoplasmic extracts by an electrophoretic mobility shift assay [40]. Soon thereafter, this activity was detected in most tissues and cell lines examined, and reported in the literature with various confusing names IRE-binding protein (IRE-BP) [79], iron regulatory factor ... 

These results first suggest that NO exhibits different effects on IRPl than peroxynitrite and ROS in vitro, and appears to promote at least a partial switch of cytosolic aconitase to IRE-binding protein. This switch is based on the disassembly of the [4Fe-4S] cluster of IRPl beyond the [3Fe-4S] stage. In contrast to NO, more potent oxidants such as peroxynitrite, superoxide or H2O2 seem to have the capacity to attack Fea and convert the [4Fe-4S] cluster to [3Fe-4S] in vitro. This oxidation is antagonized by aconitase substrates and suffices to inactivate aconitase, but not to induce IRE-binding activity. 

The above data emphasize the different effects of NO and ROS (including peroxynitrite) on IRPl in vitro, and furthermore suggest that the switch of cytosolic aconitase to IRE-binding protein in vivo, in response to extracellular H2O2, cannot be attributed to a direct removal of the 4Fe-4S cluster by intracellular ROS. 

Outline the role of RNA secondary structure in the regulation of iron metabolism in animals. Describe the roles of transferrin, transferrin receptor, ferritin, the iron-response element, and IRE-binding protein. Relate the IRE-binding protein to aconitase and iron sensing. 

The IRE is a sequence in the 5 -untranslated region of the mRNA that encodes the ferritin molecule. The IRE-binding protein (IRE-BP) binds to the IRE and blocks translation. The ERE is a DNA sequence to which the estrogen-estrogen receptor complex binds to lacilitate trancription. 

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