Iron response element

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Iron response element
RF00037 Iron Response Element.svg
Predicted secondary structure and sequence conservation of IRE
Identifiers
SymbolIRE
Rfam RF00037
Other data
RNA type Cis-reg
Domain(s) Eukaryota
SO SO:0000233
PDB structures PDBe
Crystal structure of iron regulatory protein 1 in complex with ferritin H IRE-RNA, Protein Data Bank entry 2IPY. [1]

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.

Contents

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. [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

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

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

Related Research Articles

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In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of synthesizing a protein.

<span class="mw-page-title-main">Three prime untranslated region</span> Sequence at the 3 end of messenger RNA that does not code for product

In molecular genetics, the three prime untranslated region (3′-UTR) is the section of messenger RNA (mRNA) that immediately follows the translation termination codon. The 3′-UTR often contains regulatory regions that post-transcriptionally influence gene expression.

The 5′ untranslated region is the region of a messenger RNA (mRNA) that is directly upstream from the initiation codon. This region is important for the regulation of translation of a transcript by differing mechanisms in viruses, prokaryotes and eukaryotes. While called untranslated, the 5′ UTR or a portion of it is sometimes translated into a protein product. This product can then regulate the translation of the main coding sequence of the mRNA. In many organisms, however, the 5′ UTR is completely untranslated, instead forming a complex secondary structure to regulate translation.

Eukaryotic translation is the biological process by which messenger RNA is translated into proteins in eukaryotes. It consists of four phases: initiation, elongation, termination, and recapping.

<span class="mw-page-title-main">Human iron metabolism</span> Iron metabolism in the body

Human iron metabolism is the set of chemical reactions that maintain human homeostasis of iron at the systemic and cellular level. Iron is both necessary to the body and potentially toxic. Controlling iron levels in the body is a critically important part of many aspects of human health and disease. Hematologists have been especially interested in systemic iron metabolism, because iron is essential for red blood cells, where most of the human body's iron is contained. Understanding iron metabolism is also important for understanding diseases of iron overload, such as hereditary hemochromatosis, and iron deficiency, such as iron-deficiency anemia.

Eukaryotic initiation factors (eIFs) are proteins or protein complexes involved in the initiation phase of eukaryotic translation. These proteins help stabilize the formation of ribosomal preinitiation complexes around the start codon and are an important input for post-transcription gene regulation. Several initiation factors form a complex with the small 40S ribosomal subunit and Met-tRNAiMet called the 43S preinitiation complex. Additional factors of the eIF4F complex recruit the 43S PIC to the five-prime cap structure of the mRNA, from which the 43S particle scans 5'-->3' along the mRNA to reach an AUG start codon. Recognition of the start codon by the Met-tRNAiMet promotes gated phosphate and eIF1 release to form the 48S preinitiation complex, followed by large 60S ribosomal subunit recruitment to form the 80S ribosome. There exist many more eukaryotic initiation factors than prokaryotic initiation factors, reflecting the greater biological complexity of eukaryotic translation. There are at least twelve eukaryotic initiation factors, composed of many more polypeptides, and these are described below.

<span class="mw-page-title-main">C-sis internal ribosome entry site (IRES)</span>

The c-sis internal ribosome entry site (IRES) is a RNA element found in the 5' UTR of the PDGF beta chain gene. The internal ribosome entry site contains three modules that can individually mediate internal ribosome entry. However, the full length sequence is required for maximal IRES activity. It is thought that the three IRES elements are somehow responsive to cellular changes and act to regulate the level of translation.

<span class="mw-page-title-main">GAIT element</span>

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<span class="mw-page-title-main">P27 cis-regulatory element</span>

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<span class="mw-page-title-main">Repression of heat shock gene expression (ROSE) element</span>

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<span class="mw-page-title-main">Iron-responsive element-binding protein</span> Protein family

The iron-responsive element-binding proteins, also known as IRE-BP, IRBP, IRP and IFR , bind to iron-responsive elements (IREs) in the regulation of human iron metabolism.

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<span class="mw-page-title-main">Matthias Hentze</span> German scientist

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<span class="mw-page-title-main">Red clover necrotic mosaic virus translation enhancer elements</span>

Red clover necrotic mosaic virus (RCNMV) contains several structural elements present within the 3′ and 5′ untranslated regions (UTR) of the genome that enhance translation. In eukaryotes transcription is a prerequisite for translation. During transcription the pre-mRNA transcript is processes where a 5′ cap is attached onto mRNA and this 5′ cap allows for ribosome assembly onto the mRNA as it acts as a binding site for the eukaryotic initiation factor eIF4F. Once eIF4F is bound to the mRNA this protein complex interacts with the poly(A) binding protein which is present within the 3′ UTR and results in mRNA circularization. This multiprotein-mRNA complex then recruits the ribosome subunits and scans the mRNA until it reaches the start codon. Transcription of viral genomes differs from eukaryotes as viral genomes produce mRNA transcripts that lack a 5’ cap site. Despite lacking a cap site viral genes contain a structural element within the 5’ UTR known as an internal ribosome entry site (IRES). IRES is a structural element that recruits the 40s ribosome subunit to the mRNA within close proximity of the start codon.

<span class="mw-page-title-main">RMF RNA motif</span>

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<span class="mw-page-title-main">CspA mRNA 5′ UTR</span>

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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. 1 2 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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  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.
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  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. ↑ 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. doi:10.1093/nar/gkq371. ISSN   0305-1048. PMC   2896125 . PMID   20460462.
  23. ↑ R. Leipuviene & E. C. Theil (November 2007). "The family of iron responsive RNA structures regulated by changes in cellular iron and oxygen". Cellular and Molecular Life Sciences . 64 (22): 2945–2955. doi:10.1007/s00018-007-7198-4. PMID   17849083. S2CID   30770865.
  24. ↑ 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.
  25. ↑ 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.
  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.
  28. ↑ 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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