RegRNA
A Regulatory RNA Motifs and Elements Finder
  Release 1.0, Jan 2006
 
 
 

Accession R0002
Feature Type RegRNA in 5'-UTR
Name Iron Responsive Element (IRE)
Regulatory Motif
parms

	wc += gu;


descr

	h5(minlen=2, maxlen=8)

		ss(minlen=1, maxlen=3, seq="C$")

	h5(len=5)

		ss(seq="^CAGWGH$")

	h3

		ss(minlen=0, maxlen=1)

	h3

Description The "iron-responsive element" (IRE) is a particular hairpin structure located in the 5'-untranslated region (5'-UTR) or in the 3'-untranslated region (3'-UTR) of various mRNAs coding for proteins involved in cellular iron metabolism. The IREs are recognized by trans-acting proteins known as Iron Regulatory Proteins (IRPs) that control mRNA translation rate and stability. Two closely related IRPs, denoted as IRP-1 and IRP-2, have been identified so far which bind IREs and become inactivated (IRP-1) or degradated (IRP-2) when the iron level in the cell increases. IRPs show a significant degree of similarity to mitochondrial aconitase (EC 4.2.1.3). It has been shown that under high iron conditions IRP-1, which contains a 4Fe-4S cluster that possibly acts as a cellular iron biosensor, has enzymatic activity and may act as a cytosolic aconitase. Cellular iron homeostasis in mammalian cells is maintained by the coordinate regulation of the expression of "Transferrin receptor", which determines the amount of iron acquired by the cell, and of "Ferritin", an iron storage protein, which determines the degree of intracellular iron sequestration. Thus if the cell requires more iron, the level of transferrin receptor has to increase and conversely the level of ferritin has to decrease. Ferritin, in vertebrates, consists of 24 protein subunits of two types, type H with Mr of 21 kDa and type L with Mr of 19-20 kDa. The apoprotein (Mr 450 kDa) is able to store up to 4500 Fe (III) atoms. The 5'-UTR of H- and L ferritin mRNAs contain one IRE whereas multiple IREs are located in the 3'-UTR of transferrin receptor mRNA. In the case of low iron concentration, IRPs are able to bind the IREs in the 5'-UTR of H- and L-Ferritin mRNAs repressing their translation and the IREs in the 3'-UTR of transferrin mRNA increasing its stability. Conversely, if iron concentration is high, IRP binding is diminished, which increases translation of ferritins and downregulate expression of the transferrin receptor. IREs have also been found in the mRNAs of other proteins involved in iron metabolism like "erythroid 5-aminolevulinic-acid synthase (eALAS) " involved in heme biosynthesis, the mRNA encoding the mitochondrial aconitase (a citric acid cycle enzyme) and the mRNA encoding the iron-sulfur subunit of succinate dehydrogenase (another citric acid cycle enzyme) in Drosophila melanogaster. Two alternative IRE consensus have been found. In certain IREs the bulge is best drawn with a single unpaired cytosine, whereas in others the cytosine nucleotide and two additional bases seem to oppose one free 3' nucleotide. Some evidences also suggest a structured loop with an interaction between nucleotide one and nucleotide five (in boldcase). G W G W A G A G C H C H NN NN NN NN NN NN NN NN NN NN C C NN N N NN N NN NN NN NN NN NN The lower stem can be of variable length and is AU-rich in transferrin mRNA. W=A,U and D=not G.
References Hentze MW, and Kühn LC
Molecular control of vertebrate iron metabolism: mRNA-based regulatory circuits operated by iron, nitric oxide, and oxidative stress.
Proc Natl Acad Sci U S A 1996; 93(16), 8175-82   PubMed 


Department of Biological Science and Technology, Institute of Bioinformatics, National Chiao Tung University, Taiwan
Contact with Dr. Hsien-Da Huang