Structure and function of IREs, the noncoding mRNA sequences regulating synthesis of ferritin, transferrin receptor and (erythroid) 5-aminolevulinate synthase.
The synthesis of least three proteins involved in iron metabolism is coordinately regulated in animals through noncoding sequences in mRNA, the IREs; the transcription of the genes encoding the proteins are also regulated. Cellular iron is the best known effector of changes in regulation of mRNA with IREs. A hairpin loop is the secondary structure of IRES which conserve the hairpin loop sequence, CAGUGU/C. However, variable stem sequences, apparently related to mRNA-specific function, create a family of IRE regulatory sequences. At least three types of proteins recognize IRE regions: (1) Nucleases which degrade mRNAs with 3' noncoding IRES; the IRE/IRE-BP stabilizes mRNAs with 3' noncoding IRES (transferrin receptor mRNA). (2) Initiation factors/ribosomes; the IRE/IRE-BP blocks ribosome binding of mRNAs with 5' noncoding IREs (ferritin, eALAS mRNAs). (3) Initiation factors to enhance translation (ferritin mRNA) when the IRE-BP does not bind; the ferritin IRE is thus both a negative and positive control element depending on which type of protein is bound. The IRE in ferritin mRNA is the most studied IRE to date. Site-directed mutagenesis shows that sites throughout the IRE alter negative control and IRE-BP binding reflecting the fact that the footprint of the IRE-BP is over the entire IRE. Base paired flanking regions (FL) which are ferritin IRE specific, enhance the effects of IRE-BP binding on negative control. Positive control is altered by modifying the single sites in stem/internal loop but not in the hairpin loop.(ABSTRACT TRUNCATED AT 250 WORDS)
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Department of Biochemistry, North Carolina State University, Raleigh 27695-7622.
McKenzie
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Sierzputowska-Gracz
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D000624:5-Aminolevulinate Synthetase / Q000096:biosynthesis*; D000818:Animals; D001483:Base Sequence; D017124:Conserved Sequence; D004912:Erythrocytes / Q000201:enzymology; D005293:Ferritins / Q000096:biosynthesis*; D006801:Humans; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009690:Nucleic Acid Conformation; D010802:Phylogeny; D012333:RNA, Messenger / Q000737:chemistry* / Q000378:metabolism*; D011990:Receptors, Transferrin / Q000096:biosynthesis*; D012045:Regulatory Sequences, Nucleic Acid; D012270:Ribosomes / Q000378:metabolism; D012689:Sequence Homology, Nucleic Acid
D012333:RNA, Messenger; D011990:Receptors, Transferrin; D005293:Ferritins; D000624:5-Aminolevulinate Synthetase