The iron regulatory region of ferritin mRNA is also a positive control element for iron-independent translation

Fe 2+ binds iron responsive element-RNA, selectively changing protein-binding affinities and regulating mRNA repression and activation

“…High-affinity eIF4F binding to ferritin IRE-RNA, even without the m 7 G cap (Fig. 3A), explains the previous observation that omitting the cap of IRE-RNA has little effect on protein synthesis contrasting with the large effect of deleting the IRE-RNA structure (14).…”

“…Fe 2þ -induced release of IRP binding alone is insufficient to account for IRE-stimulation of ferritin synthesis in vitro (14) and for the larger iron response of ferritin in vivo, compared to other IRE-mRNAs (7). If IRE-RNA bound a protein synthesis initiation factor, the large iron response in vivo and the approximately 10-fold decrease in IRP-independent synthesis associated with IRE deletion (14), would be explained.…”

“…If IRE-RNA bound a protein synthesis initiation factor, the large iron response in vivo and the approximately 10-fold decrease in IRP-independent synthesis associated with IRE deletion (14), would be explained. The effects of IRE deletion occur in both rabbit reticulocytes which contains endogenous IRP and in WGE without endogenous IRP, indicating a common component.…”

“…IRP proteins bind with different stabilities to IRE-RNAs of the IRE-RNA family (12,13), creating a graded or hierarchal set of mRNA responses to iron in vivo. Deletion of the 30 nt IRE-RNA not only removes IRP regulation but also decreases the rate of IRP-independent protein synthesis (14). A number of current models of IRE-RNA/IRP regulation feature iron-dependent degradation/modification of the IRP proteins as the main control point (8,9,15,16).…”

“…Overlap of the IRE-RNA and the Fe-S binding sites on IRP1 prevents Fe-S insertion in the IRP1/IRE-RNA complex (5). (ii) How does the IRE-RNA control rates of IRP-independent protein synthesis (14)? In an earlier study, we showed that Fe 2þ ions (anaerobic) selectively increased the dissociation constant for the IRE-RNA/IRP1 complex in solution (12).…”