Iron response element explained

Iron response element
Symbol:IRE
Rfam:RF00037
Rna Type:Cis-reg
Tax Domain:Eukaryota

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.

Mechanism of action

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.[1] There is variation in affinity between different IREs and different IRPs.[2]

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.[3] Several studies have identified non-canonical IREs.[4] It has also been shown that IRP binds to some IREs better than others.[5]

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).[6] 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.[7] 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[8] have been created for the IRE—one with a bulged U and one without.

Genes with IREs

Genes known to contain IREs include FTH1,[9] FTL,[10] TFRC,[11] ALAS2,[12] Sdhb,[13] ACO2,[14] Hao1,[15] SLC11A2 (encoding DMT1), NDUFS1,[16] SLC40A1 (encoding the ferroportin)[17] CDC42BPA,[18] CDC14A,[19] EPAS1.[20]

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.[21]

Taxonomic range. The IRE is found over a diverse taxonomic range—mainly eukaryotes but not in plants.[22]

Processes regulated by IREs

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.[23] EPAS1 encodes a transcription factor involved in complex oxygen sensing pathways by the induction of oxygen regulated genes under low oxygen conditions.[24] CDC42BPA encodes a kinase with a role in cytoskeletal reorganisation.[25] CDC14A encodes a dual-specificity phosphatase implicated in cell cycle control[26] and also interacts with interphase centrosomes.[27]

See also

External links

Notes and References

  1. Martina U. Muckenthaler . Bruno Galy. Bruno Galy. Matthias W. Hentze. Matthias W. Hentze. amp . Systemic iron homeostasis and the iron-responsive element/iron-regulatory protein (IRE/IRP) regulatory network . . 28 . 197–213 . 2008 . 10.1146/annurev.nutr.28.061807.155521 . 18489257. Martina U. Muckenthaler.
  2. H. Gunshin . C. R. Allerson. M. Polycarpou-Schwarz. M. Polycarpou-Schwarz . A. Rofts. A. Rofts. J. T. Rogers. J. T. Rogers. F. Kishi. F. Kishi. M. W. Hentze. M. W. Hentze. T. A. Rouault. T. A. Rouault. N. C. Andrews. N. C. Andrews . M. A. Hediger. M. A. Hediger. amp . Iron-dependent regulation of the divalent metal ion transporter . . 509 . 2 . 309–316 . December 2001 . 11741608 . 10.1016/s0014-5793(01)03189-1. C. R. Allerson. H. Gunshin. free.
  3. 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. en. 109. 22. 8417–8422. 10.1073/pnas.1120045109. 0027-8424. 3365203 . 22586079. free.
  4. Campillos. M.. Cases. I.. Hentze. M. W.. Sanchez. M.. 2010-07-01. SIREs: searching for iron-responsive elements. Nucleic Acids Research. en. 38. Web Server. W360–W367. 10.1093/nar/gkq371. 0305-1048. 2896125 . 20460462.
  5. 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. en. 42. 10. 6567–6577. 10.1093/nar/gku248. 0305-1048. 4041422 . 24728987.
  6. T. S. Huang. O. Melefors. M. I. Lind. M. I. Lind . K. Soderhall. K. Soderhall. amp . An atypical iron-responsive element (IRE) within crayfish ferritin mRNA and an iron regulatory protein 1 (IRP1)-like protein from crayfish hepatopancreas . . 29 . 1 . 1–9 . January 1999 . 10070739 . 10.1016/S0965-1748(98)00097-6. O. Melefors. T. S. Huang.
  7. K. J. Addess. J. P. Basilion. R. D. Klausner. R. D. Klausner . T. A. Rouault. T. A. Rouault . A. Pardi. A. Pardi. amp . Structure and dynamics of the iron responsive element RNA: implications for binding of the RNA by iron regulatory binding proteins . . 274 . 1 . 72–83 . November 1997 . 10.1006/jmbi.1997.1377 . 9398517. J. P. Basilion. K. J. Addess.
  8. Two covariance models for iron-responsive elements . . 8 . 5 . 792–801 . September 2011 . 21881407 . Stevens SG, Gardner PP, Brown C . 10.4161/rna.8.5.16037 . free .
  9. M. W. Hentze. S. W. Caughman. T. A. Rouault. T. A. Rouault . J. G. Barriocanal. J. G. Barriocanal . A. Dancis. A. Dancis . J. B. Harford. J. B. Harford . R. D. Klausner. R. D. Klausner. amp . Identification of the iron-responsive element for the translational regulation of human ferritin mRNA . . 238 . 4833 . 1570–1573 . December 1987 . 3685996 . 10.1126/science.3685996. S. W. Caughman. M. W. Hentze.
  10. N. Aziz . H. N. Munro . amp . Iron regulates ferritin mRNA translation through a segment of its 5' untranslated region . . 84 . 23 . 8478–8482 . December 1987 . 3479802 . 299567 . 10.1073/pnas.84.23.8478. H. N. Munro . N. Aziz . free .
  11. D. M. Koeller. J. L. Casey. M. W. Hentze. M. W. Hentze . E. M. Gerhardt. E. M. Gerhardt . L. N. Chan. L. N. Chan . R. D. Klausner. R. D. Klausner . J. B. Harford. J. B. Harford. amp . A cytosolic protein binds to structural elements within the iron regulatory region of the transferrin receptor mRNA . . 86 . 10 . 3574–3578 . May 1989 . 2498873 . 287180 . 10.1073/pnas.86.10.3574. J. L. Casey. D. M. Koeller. free.
  12. T. Dandekar. R. Stripecke. N. K. Gray. N. K. Gray . B. Goossen. B. Goossen . A. Constable. A. Constable . H. E. Johansson. H. E. Johansson . M. W. Hentze. M. W. Hentze . amp . Identification of a novel iron-responsive element in murine and human erythroid delta-aminolevulinic acid synthase mRNA . . 10 . 7 . 1903–1909 . July 1991 . 2050126 . 452865. 10.1002/j.1460-2075.1991.tb07716.x. R. Stripecke. T. Dandekar.
  13. S. A. Kohler . B. R. Henderson . L. C. Kuhn . L. C. Kuhn. amp . Succinate dehydrogenase b mRNA of Drosophila melanogaster has a functional iron-responsive element in its 5'-untranslated region . . 270 . 51 . 30781–30786 . December 1995 . 8530520 . 10.1074/jbc.270.51.30781. B. R. Henderson . S. A. Kohler . free .
  14. N. K. Gray. K. Pantopoulos . T. Dandekar . T. Dandekar . B. A. Ackrell . B. A. Ackrell . M. W. Hentze . M. W. Hentze . amp . Translational regulation of mammalian and Drosophila citric acid cycle enzymes via iron-responsive elements . . 93 . 10 . 4925–4930 . May 1996 . 8643505 . 39381 . 10.1073/pnas.93.10.4925. K. Pantopoulos . N. K. Gray . free .
  15. S. A. Kohler . E. Menotti . L. C. Kuhn . L. C. Kuhn . amp . Molecular cloning of mouse glycolate oxidase. High evolutionary conservation and presence of an iron-responsive element-like sequence in the mRNA . . 274 . 4 . 2401–2407 . January 1999 . 9891009 . 10.1074/jbc.274.4.2401. E. Menotti . S. A. Kohler . free .
  16. E. Lin . J. H. Graziano . G. A. Freyer . G. A. Freyer . amp . Regulation of the 75-kDa subunit of mitochondrial complex I by iron . . 276 . 29 . 27685–27692 . July 2001 . 10.1074/jbc.M100941200 . 11313346. J. H. Graziano . E. Lin . free .
  17. Athina Lymboussaki . Elisa Pignatti . Giuliana Montosi . Giuliana Montosi . Cinzia Garuti . Cinzia Garuti . David J. Haile . David J. Haile . Antonello Pietrangelo . Antonello Pietrangelo . amp . The role of the iron responsive element in the control of ferroportin1/IREG1/MTP1 gene expression . . 39 . 5 . 710–715 . November 2003 . 14568251 . 10.1016/S0168-8278(03)00408-2. Elisa Pignatti . Athina Lymboussaki .
  18. Radek Cmejla . Jiri Petrak . Jana Cmejlova . Jana Cmejlova . amp . A novel iron responsive element in the 3'UTR of human MRCKalpha . . 341 . 1 . 158–166 . March 2006 . 10.1016/j.bbrc.2005.12.155 . 16412980. Jiri Petrak . Radek Cmejla .
  19. Mayka Sanchez . Bruno Galy . Thomas Dandekar . Thomas Dandekar . Peter Bengert . Peter Bengert . Yevhen Vainshtein . Yevhen Vainshtein . Jens Stolte . Jens Stolte . Martina U. Muckenthaler . Martina U. Muckenthaler . Matthias W. Hentze . Matthias W. Hentze . amp . 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 . . 281 . 32 . 22865–22874 . August 2006 . 10.1074/jbc.M603876200 . 16760464. Bruno Galy . Mayka Sanchez . free .
  20. Mayka Sanchez . Bruno Galy . Martina U. Muckenthaler . Martina U. Muckenthaler . Matthias W. Hentze . Matthias W. Hentze . amp . Iron-regulatory proteins limit hypoxia-inducible factor-2alpha expression in iron deficiency . . 14 . 5 . 420–426 . May 2007 . 10.1038/nsmb1222 . 17417656. 37819604 . Bruno Galy . Mayka Sanchez .
  21. Campillos. Monica. Cases. Ildefonso. Hentze. Matthias W.. Sanchez. Mayka. 2010-07-01. SIREs: searching for iron-responsive elements. Nucleic Acids Research. 38. Web Server issue. W360–W367. 10.1093/nar/gkq371. 0305-1048. 2896125 . 20460462.
  22. R. Leipuviene . E. C. Theil . amp . The family of iron responsive RNA structures regulated by changes in cellular iron and oxygen . . 64 . 22 . 2945–2955 . November 2007 . 10.1007/s00018-007-7198-4 . 17849083. 30770865 . E. C. Theil . R. Leipuviene . 11136088 .
  23. M. J. Gruer . P. J. Artymiuk . J. R. Guest . J. R. Guest . amp . The aconitase family: three structural variations on a common theme . . 22 . 1 . 3–6 . January 1997 . 9020582 . 10.1016/S0968-0004(96)10069-4. P. J. Artymiuk . M. J. Gruer .
  24. Amar J. Majmundar . Waihay J. Wong . Waihay J. Wong . M. Celeste Simon . M. Celeste Simon . amp . Hypoxia-inducible factors and the response to hypoxic stress . . 40 . 2 . 294–309 . October 2010 . 10.1016/j.molcel.2010.09.022 . 20965423 . 3143508. Amar J. Majmundar .
  25. T. Leung . X. Q. Chen. I. Tan. I. Tan. E. Manser. E. Manser . L. Lim. L. Lim. amp . Myotonic dystrophy kinase-related Cdc42-binding kinase acts as a Cdc42 effector in promoting cytoskeletal reorganization . . 18 . 1 . 130–140 . January 1998 . 9418861 . 121465 . 10.1128/mcb.18.1.130. X. Q. Chen. T. Leung.
  26. J. Bembenek . H. Yu . amp . Regulation of the anaphase-promoting complex by the dual specificity phosphatase human Cdc14a . . 276 . 51 . 48237–48242 . December 2001 . 10.1074/jbc.M108126200 . 11598127. H. Yu . J. Bembenek . free .
  27. Niels Mailand . Claudia Lukas . Brett K. Kaiser . Brett K. Kaiser . Peter K. Jackson . Peter K. Jackson . Jiri Bartek . Jiri Bartek . Jiri Lukas . Jiri Lukas . amp . Deregulated human Cdc14A phosphatase disrupts centrosome separation and chromosome segregation . . 4 . 4 . 317–322 . April 2002 . 10.1038/ncb777 . 11901424. 28955777 . Claudia Lukas . Niels Mailand .

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