Iron regulatory proteins IRP-1 and

How Does NO and H2O2 Affect the Iron Regulatory Proteins IRP-1 and IRP-2... 

The iron regulatory proteins, IRP-1 and IRP-2, bind at high affinity (Kd 40-100 pM) to highly conserved RNA stemloops, the Iron-responsive Elements (IREs) at the 5 cap sites of the L- and H-ferritin niRNAs [55-57] (Figure 2). The IRE/IRP interaction impedes the access of the small 40S ribosome subunit to the 5 end of the ferritin niRNAs and thereby suppresses L- and H-ferritin mRNA translation [58-60]. The potency of the IRE to regulate translation is position dependent [61]. Iron influx relieves repression of ferritin translation by removing IRP-1 from the ferritin IREs IRP-1 is simultaneously interconverted to a cytoplasmic cis-aconitase with an iron sulfur cluster, and IRP-2 is degraded by... 

In the EPR of mammalian cells, we do not see much in addition to the signals from the respiratory complexes. The enzyme aconitase from the citric-acid cycle can be detected, and also the protein cytoplasmic aconitase, later identified as the mRNA translation regulatory factor iron regulatory protein IRP-1, which actually started its career in biochemistry as an EPR signal that could not be assigned to the respiratory chain (Kennedy et al. 1992). 

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]. 

Iron regulatory protein (IRP)-l RNA-binding activity was induced by nitric oxide (Drapier et al. 1993, Weiss et al. 1993). Activation in cells required a time of treatment similar to desferrioxamine, and while it remains possible that NO indirectly induces IRP-1 via modulation of intracellular iron levels, the in vitro analysis of recombinant IRP-1 suggested that NO can direct affect the [Fe-S] cluster (Drapier et al. 1993). 

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