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The role of IRE and flanking region structure in translational repression of ferritin mRNA
Author(s) -
Leipuviene Ramune,
Long Joanne C.,
Theil Elizabeth C.
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.a931-a
Subject(s) - messenger rna , chemistry , microbiology and biotechnology , ferritin , translation (biology) , base pair , biology , dna , biochemistry , gene
Ferritin (Frt) concentrates Fe for iron‐protein synthesis and protects cells from Fe and O2 induced radicals. Frt expression is regulated at transcription and translation by numerous signals. Regulation of Frt mRNA depends on Iron Regulating Proteins (IRPs) and the Iron Regulatory Element (IRE) in the 5′UTR. The Frt IRE is a mRNA structure comprised of a terminal hexaloop and stem of 10 base pairs interrupted by an internal loop/bulge (IL/B). The Frt IRE is structurally integrated with a base‐paired flanking region (FL) of variable length, which positions the IRE+FL 10–20 nucleotides from the mRNA cap. There are two Frt subunit types in animals: catalytically active (H) and catalytically inactive (L). The H:L ratio is tissue specific. H:L protein composition diverges ~ 10 fold from the H:L mRNA composition, suggesting differential translation. in vitro studies demonstrate H:L translation efficiency differs by 1.5‐2 fold. We sought structural differences in H and L IRE+FL structures that related to differential translation/derepression in vitro, using Cu(phen)2 probing, mRNA‐IRP binding and mutagenesis. The results showed that in contrast to H‐IRE, L‐IRE contains a more flexible IL/B, which was recognized and efficiently repressed by IRP2, and appears to relate to the IL/B closing base‐pair U‐G or C‐G and the conserved triplet of base pairs CUC‐GAG or CCC‐GGG. The combination of the C‐G and GAG‐CUC base pairs in IRE+FL explain, in part, the enhanced efficiency of H‐Frt translation and the significance of IRE substructure in translation regulation. Part support NIH DK20251.