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::General Information
ID U0002
Creation Date 30 July 1997
Updating Date 28 September 2009
Standard Name Iron Responsive Element (IRE)
UTRSite Pattern
r1={au,ua,gc,cg,gu,ug}
(p1=2...8 c p2=5...5 CAGWGH r1~p2 r1~p1 | 
p3=2...8 nnc p4=5...5 CAGWGH r1~p4 n r1~p3 |
p5=6...8 c p6=2...2 p7=3...3 CAGWGH r1~p7 u r1~p6 r1~p5 )
Random Expectation 0.0005537610 hits/kb
::Taxonomy
UTR Region All
Taxon Range Metazoa
::Description
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 5' and 3'UTRs of mRNAs encoding other proteins involved in iron metabolism such as divalent metal transporter 1 (DMT1-, DCT1-, NRAMP2-, SLC11A2), erythroid 5-aminolevulinic-acid synthase (eALAS) , cell division cycle 14A (CDC14A), mitochondrial aconitase, Drosophila succinate dehydrogenase, and iron regulated transporters (FPN1-, IREG1-, MTP1-, SLC40A1). Two major 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 C1 and G5. The lower stem can be of variable length and is AU-rich in transferrin mRNA (see Figure, W=A,U and D=not G).

To be noted that a variant IRE structure has been identified in specific alternative splicing mRNA isoforms of the SLC11A2 gene.

Image
::Features
Feature Key IRE
::Database Cross-references
Link
RFAM: RF00037
::Transcript(s) / Gene(s)
UTR(s)
Description Species Link Ref.
5'UTR in Homo sapiens ferritin, heavy polypeptide 1 (FTH1), mRNA. Homo sapiens UTRef: 5HSAR020849 [U1][U2]
3'UTR in Homo sapiens transferrin receptor (p90, CD71) (TFRC), mRNA. Homo sapiens UTRef: 3HSAR032186 [U3][U4]
Transcript(s)
Description Species Link Ref.
Homo sapiens ferritin, heavy polypeptide 1 (FTH1), mRNA. Homo sapiens RefSeq: NM_002032
Homo sapiens transferrin receptor (p90, CD71) (TFRC), mRNA Homo sapiens RefSeq: NM_003234
Gene(s)
Description Species Link Ref.
Ferritin H subunit (FTH1) Homo sapiens ENSEMBL: ENSG00000167996
Transferrin receptor protein 1 (TfR1, TR, TfR, Trfr, CD71 antigen, T9, p90) Homo sapiens ENSEMBL: ENSG00000072274
::Protein(s)
Binding Protein(s)
Description Species Link Ref.
Iron-responsive element-binding protein 1 Homo sapiens UniProt: P21399 [B1]
Iron-responsive element-binding protein 2 Homo sapiens UniProt: P48200 [B2]
::References
ID [1]
Authors Hentze M.W. and Kuhn L.C.
Title Molecular control of vertebrate iron metabolism: mRNA based regulatory circuits operated by iron, nitric oxide, and oxidative stress
Citation Proc. Natl. Acad. Sci. USA 93: 8175-8182
Year 1996
ID [2]
Authors Sanchez M, Galy B, Dandekar T, Bengert P, Vainshtein Y, Stollte J Muckenthaler MU, Hentze MW.
Title Iron regulation and the cell cycle: Identification of an iron-responsive element in the 3' untranslated region of human cell division cycle 14A mRNA by a refined microarray-based screening strategy.
Citation J Biol Chem. 2006
Year 2006
ID [3]
Authors Gunshin H, Allerson CR, Polycarpou-Schwarz M, Rofts A, Rogers JT, Kishi F, Hentze MW, Rouault TA, Andrews NC, Hediger MA.
Title Iron-dependent regulation of the divalent metal ion transporter.
Citation FEBS Lett. 2001 Dec 7; 509(2): 309-16
Year 2001
ID [U1]
Authors Hentze M.W. and Kuhn L.C.
Title Molecular control of vertebrate iron metabolism: mRNA based regulatory circuits operated by iron, nitric oxide, and oxidative stress
Citation Proc. Natl. Acad. Sci. USA 93: 8175-8182
Year 1996
ID [U2]
Authors Hentze MW, Muckenthaler MU, Andrews NC.
Title Balancing acts: molecular control of mammalian iron metabolism.
Citation Cell 2004 Apr 30; 117(3): 285-97
Year 2004
ID [U3]
Authors Hentze M.W. and Kuhn L.C.
Title Molecular control of vertebrate iron metabolism: mRNA based regulatory circuits operated by iron, nitric oxide, and oxidative stress
Citation Proc. Natl. Acad. Sci. USA 93: 8175-8182
Year 1996
ID [U4]
Authors Hentze MW, Muckenthaler MU, Andrews NC.
Title Balancing acts: molecular control of mammalian iron metabolism.
Citation Cell 2004 Apr 30; 117(3): 285-97
Year 2004
ID [B1]
Authors Hentze MW, Muckenthaler MU, Andrews NC.
Title Balancing acts: molecular control of mammalian iron metabolism.
Citation Cell 2004 Apr 30; 117(3): 285-97
Year 2004
ID [B2]
Authors Hentze MW, Muckenthaler MU, Andrews NC.
Title Balancing acts: molecular control of mammalian iron metabolism.
Citation Cell 2004 Apr 30; 117(3): 285-97
Year 2004