Iron response element

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

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] Some IREs can also be affected by alternative gene splicing. In the second theory, There are two proteins competing for the IRE binding site—both IRP and eukaryotic Initiation Factor F4 (eIFF4). 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 eIFF4.[4] Several studies have identified non-canonical IREs.[5] It has also been shown that IRP binds to some IREs better than others.[6]

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 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] Many of these genes 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.[22] EPAS1 encodes a transcription factor involved in complex oxygen sensing pathways by the induction of oxygen regulated genes under low oxygen conditions.[23] CDC42BPA encodes a kinase with a role in cytoskeletal reorganisation.[24] CDC14A encodes a dual-specificity phosphatase implicated in cell cycle control[25] and also interacts with interphase centrosomes.[26]

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.[27]

The IRE is found over a diverse taxonomic range—mainly eukaryotes but not in plants.[28]

See also

References
  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. 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.
  7. T. S. Huang; O. Melefors; M. I. Lind & K. Soderhall (January 1999). "An atypical iron-responsive element (IRE) within crayfish ferritin mRNA and an iron regulatory protein 1 (IRP1)-like protein from crayfish hepatopancreas". Insect Biochemistry and Molecular Biology. 29 (1): 1–9. doi:10.1016/S0965-1748(98)00097-6. PMID 10070739.
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  9. Stevens SG, Gardner PP, Brown C (September 2011). "Two covariance models for iron-responsive elements". RNA Biology. 8 (5): 792–801. doi:10.4161/rna.8.5.16037. PMID 21881407.
  10. M. W. Hentze; S. W. Caughman; T. A. Rouault; J. G. Barriocanal; A. Dancis; J. B. Harford & R. D. Klausner (December 1987). "Identification of the iron-responsive element for the translational regulation of human ferritin mRNA". Science. 238 (4833): 1570–1573. doi:10.1126/science.3685996. PMID 3685996.
  11. N. Aziz & H. N. Munro (December 1987). "Iron regulates ferritin mRNA translation through a segment of its 5' untranslated region". Proceedings of the National Academy of Sciences of the United States of America. 84 (23): 8478–8482. doi:10.1073/pnas.84.23.8478. PMC 299567. PMID 3479802.
  12. D. M. Koeller; J. L. Casey; M. W. Hentze; E. M. Gerhardt; L. N. Chan; R. D. Klausner & J. B. Harford (May 1989). "A cytosolic protein binds to structural elements within the iron regulatory region of the transferrin receptor mRNA". Proceedings of the National Academy of Sciences of the United States of America. 86 (10): 3574–3578. doi:10.1073/pnas.86.10.3574. PMC 287180. PMID 2498873.
  13. T. Dandekar; R. Stripecke; N. K. Gray; B. Goossen; A. Constable; H. E. Johansson & M. W. Hentze (July 1991). "Identification of a novel iron-responsive element in murine and human erythroid delta-aminolevulinic acid synthase mRNA". The EMBO Journal. 10 (7): 1903–1909. doi:10.1002/j.1460-2075.1991.tb07716.x. PMC 452865. PMID 2050126.
  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.
  17. E. Lin; J. H. Graziano & G. A. Freyer (July 2001). "Regulation of the 75-kDa subunit of mitochondrial complex I by iron". The Journal of Biological Chemistry. 276 (29): 27685–27692. doi:10.1074/jbc.M100941200. PMID 11313346.
  18. Athina Lymboussaki; Elisa Pignatti; Giuliana Montosi; Cinzia Garuti; David J. Haile & Antonello Pietrangelo (November 2003). "The role of the iron responsive element in the control of ferroportin1/IREG1/MTP1 gene expression". Journal of Hepatology. 39 (5): 710–715. doi:10.1016/S0168-8278(03)00408-2. PMID 14568251.
  19. Radek Cmejla; Jiri Petrak & Jana Cmejlova (March 2006). "A novel iron responsive element in the 3'UTR of human MRCKalpha". Biochemical and Biophysical Research Communications. 341 (1): 158–166. doi:10.1016/j.bbrc.2005.12.155. PMID 16412980.
  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.
  21. Mayka Sanchez; Bruno Galy; Martina U. Muckenthaler & Matthias W. Hentze (May 2007). "Iron-regulatory proteins limit hypoxia-inducible factor-2alpha expression in iron deficiency". Nature Structural & Molecular Biology. 14 (5): 420–426. doi:10.1038/nsmb1222. PMID 17417656. S2CID 37819604.
  22. M. J. Gruer; P. J. Artymiuk & J. R. Guest (January 1997). "The aconitase family: three structural variations on a common theme". Trends in Biochemical Sciences. 22 (1): 3–6. doi:10.1016/S0968-0004(96)10069-4. PMID 9020582.
  23. Amar J. Majmundar; Waihay J. Wong & M. Celeste Simon (October 2010). "Hypoxia-inducible factors and the response to hypoxic stress". Molecular Cell. 40 (2): 294–309. doi:10.1016/j.molcel.2010.09.022. PMC 3143508. PMID 20965423.
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  25. 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.
  26. Niels Mailand; Claudia Lukas; Brett K. Kaiser; Peter K. Jackson; Jiri Bartek & Jiri Lukas (April 2002). "Deregulated human Cdc14A phosphatase disrupts centrosome separation and chromosome segregation". Nature Cell Biology. 4 (4): 317–322. doi:10.1038/ncb777. PMID 11901424. S2CID 28955777.
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