Iron response element

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In molecular biology, the iron response element or iron-responsive element (IRE) is a short conserved stem-loop which is bound by iron response proteins (IRPs, also named IRE-BP or IRBP). The IRE is found in UTRs (untranslated regions) of various mRNAs whose products are involved in iron metabolism. For example, the mRNA of ferritin (an iron storage protein) contains one IRE in its 5' UTR. When iron concentration is low, IRPs bind the IRE in the ferritin mRNA and cause reduced translation rates. In contrast, binding to multiple IREs in the 3' UTR of the transferrin receptor (involved in iron acquisition) leads to increased mRNA stability.

Iron response element
Identifiers
SymbolIRE
RfamRF00037
Other data
RNA typeCis-reg
Domain(s)Eukaryota
SOSO:0000233
PDB structuresPDBe
Crystal structure of iron regulatory protein 1 in complex with ferritin H IRE-RNA, Protein Data Bank entry 2IPY.[1]

Mechanism of action

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The two leading theories describe how iron probably interacts to impact posttranslational control of transcription. The classical theory suggests that IRPs, in the absence of iron, bind avidly to the mRNA IRE. When iron is present, it interacts with the protein to cause it to release the mRNA. For example, In high iron conditions in humans, IRP1 binds with an iron-sulphur complex [4Fe-4S] and adopts an aconitase conformation unsuitable for IRE binding. In contrast, IRP2 is degraded in high iron conditions.[2] There is variation in affinity between different IREs and different IRPs.[3]

In the second theory two proteins compete for the IRE binding site—both IRP and eukaryotic Initiation Factor 4F (eIF4F). In the absence of iron IRP binds about 10 times more avidly than the initiation factor. However, when Iron interacts at the IRE, it causes the mRNA to change its shape, thus favoring the binding of the eIF4F.[4] Several studies have identified non-canonical IREs.[5] It has also been shown that IRP binds to some IREs better than others.[6]

Structural details. The upper helix of the known IREs shows stronger conservation of structure compared to the lower helix. The bases composing the helixes are variable. The mid-stem bulged C is a highly characteristic feature (though this has been seen to be a G in the ferritin IRE for lobster).[7] The apical loop of the known IREs all consist of either the AGA or AGU triplet. This is pinched by a paired G-C and there is additionally a bulged U, C or A in the upper helix. The crystal structure and NMR data show a bulged U in the lower stem of the ferritin IRE.[8] This is consistent with the predicted secondary structure. IREs in many other mRNAs do not have any support for this bulged U. Consequently, two RFAM models[9] have been created for the IRE—one with a bulged U and one without.

Genes with IREs

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Genes known to contain IREs include FTH1,[10] FTL,[11] TFRC,[12] ALAS2,[13] Sdhb,[14] ACO2,[15] Hao1,[16] SLC11A2 (encoding DMT1),[3] NDUFS1,[17] SLC40A1 (encoding the ferroportin)[18] CDC42BPA ,[19] CDC14A,[20] EPAS1.[21]

In humans, 12 genes have been shown to be transcribed with the canonical IRE structure, but several mRNA structures, that are non-canonical, have been shown to interact with IRPs and be influenced by iron concentration. Software and algorithms have been developed to locate more genes that are also responsive to iron concentration.[22]

Taxonomic range. The IRE is found over a diverse taxonomic range—mainly eukaryotes but not in plants.[23]

Processes regulated by IREs

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Many genes regulated by IREs have clear and direct roles in iron metabolism. Others show a less obvious connection. ACO2 encodes an isomerase catalysing the reversible isomerisation of citrate and isocitrate.[24] EPAS1 encodes a transcription factor involved in complex oxygen sensing pathways by the induction of oxygen regulated genes under low oxygen conditions.[25] CDC42BPA encodes a kinase with a role in cytoskeletal reorganisation.[26] CDC14A encodes a dual-specificity phosphatase implicated in cell cycle control[27] and also interacts with interphase centrosomes.[28]


See also

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References

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  1. ^ William E. Walden; Anna I. Selezneva; Jerome Dupuy; Anne Volbeda; Juan C. Fontecilla-Camps; Elizabeth C. Theil & Karl Volz (December 2006). "Structure of dual function iron regulatory protein 1 complexed with ferritin IRE-RNA". Science. 314 (5807): 1903–1908. doi:10.1126/science.1133116. PMID 17185597. S2CID 26572367.
  2. ^ Martina U. Muckenthaler; Bruno Galy & Matthias W. Hentze (2008). "Systemic iron homeostasis and the iron-responsive element/iron-regulatory protein (IRE/IRP) regulatory network". Annual Review of Nutrition. 28: 197–213. doi:10.1146/annurev.nutr.28.061807.155521. PMID 18489257.
  3. ^ a b H. Gunshin; C. R. Allerson; M. Polycarpou-Schwarz; A. Rofts; J. T. Rogers; F. Kishi; M. W. Hentze; T. A. Rouault; N. C. Andrews & M. A. Hediger (December 2001). "Iron-dependent regulation of the divalent metal ion transporter". FEBS Letters. 509 (2): 309–316. doi:10.1016/s0014-5793(01)03189-1. PMID 11741608.
  4. ^ Ma, Jia; Haldar, Suranjana; Khan, Mateen A.; Sharma, Sohani Das; Merrick, William C.; Theil, Elizabeth C.; Goss, Dixie J. (2012-05-29). "Fe2+ binds iron responsive element-RNA, selectively changing protein-binding affinities and regulating mRNA repression and activation". Proceedings of the National Academy of Sciences. 109 (22): 8417–8422. doi:10.1073/pnas.1120045109. ISSN 0027-8424. PMC 3365203. PMID 22586079.
  5. ^ Campillos, M.; Cases, I.; Hentze, M. W.; Sanchez, M. (2010-07-01). "SIREs: searching for iron-responsive elements". Nucleic Acids Research. 38 (Web Server): W360–W367. doi:10.1093/nar/gkq371. ISSN 0305-1048. PMC 2896125. PMID 20460462.
  6. ^ Khan, M. A.; Ma, J.; Walden, W. E.; Merrick, W. C.; Theil, E. C.; Goss, D. J. (2014-06-02). "Rapid kinetics of iron responsive element (IRE) RNA/iron regulatory protein 1 and IRE-RNA/eIF4F complexes respond differently to metal ions". Nucleic Acids Research. 42 (10): 6567–6577. doi:10.1093/nar/gku248. ISSN 0305-1048. PMC 4041422. PMID 24728987.
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  14. ^ S. A. Kohler; B. R. Henderson & L. C. Kuhn (December 1995). "Succinate dehydrogenase b mRNA of Drosophila melanogaster has a functional iron-responsive element in its 5'-untranslated region". The Journal of Biological Chemistry. 270 (51): 30781–30786. doi:10.1074/jbc.270.51.30781. PMID 8530520.
  15. ^ N. K. Gray; K. Pantopoulos; T. Dandekar; B. A. Ackrell & M. W. Hentze (May 1996). "Translational regulation of mammalian and Drosophila citric acid cycle enzymes via iron-responsive elements". Proceedings of the National Academy of Sciences of the United States of America. 93 (10): 4925–4930. doi:10.1073/pnas.93.10.4925. PMC 39381. PMID 8643505.
  16. ^ S. A. Kohler; E. Menotti & L. C. Kuhn (January 1999). "Molecular cloning of mouse glycolate oxidase. High evolutionary conservation and presence of an iron-responsive element-like sequence in the mRNA". The Journal of Biological Chemistry. 274 (4): 2401–2407. doi:10.1074/jbc.274.4.2401. PMID 9891009.
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  20. ^ Mayka Sanchez; Bruno Galy; Thomas Dandekar; Peter Bengert; Yevhen Vainshtein; Jens Stolte; Martina U. Muckenthaler & Matthias W. Hentze (August 2006). "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". The Journal of Biological Chemistry. 281 (32): 22865–22874. doi:10.1074/jbc.M603876200. PMID 16760464.
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  26. ^ T. Leung; X. Q. Chen; I. Tan; E. Manser & L. Lim (January 1998). "Myotonic dystrophy kinase-related Cdc42-binding kinase acts as a Cdc42 effector in promoting cytoskeletal reorganization". Molecular and Cellular Biology. 18 (1): 130–140. doi:10.1128/mcb.18.1.130. PMC 121465. PMID 9418861.
  27. ^ J. Bembenek & H. Yu (December 2001). "Regulation of the anaphase-promoting complex by the dual specificity phosphatase human Cdc14a". The Journal of Biological Chemistry. 276 (51): 48237–48242. doi:10.1074/jbc.M108126200. PMID 11598127.
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