iron response element

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.{{Cite journal

| author1 = Martina U. Muckenthaler | author2-link=Bruno Galy| author2=Bruno Galy| author3-link=Matthias W. Hentze|author3=Matthias W. Hentze|name-list-style=amp

| title = Systemic iron homeostasis and the iron-responsive element/iron-regulatory protein (IRE/IRP) regulatory network

| journal = Annual Review of Nutrition

| volume = 28

| pages = 197–213

| date= 2008 | doi = 10.1146/annurev.nutr.28.061807.155521

| pmid = 18489257

| author1-link=Martina U. Muckenthaler}} There is variation in affinity between different IREs and different IRPs.{{Cite journal

| author = H. Gunshin | author2=C. R. Allerson| author3-link=M. Polycarpou-Schwarz|author3=M. Polycarpou-Schwarz | author4-link=A. Rofts| author4= A. Rofts| author5-link=J. T. Rogers|author5=J. T. Rogers| author6-link=F. Kishi|author6= F. Kishi| author7-link=M. W. Hentze|author7=M. W. Hentze| author8-link=T. A. Rouault|author8= T. A. Rouault| author9-link=N. C. Andrews|author9=N. C. Andrews | author10-link=M. A. Hediger|author10= M. A. Hediger|name-list-style=amp

| title = Iron-dependent regulation of the divalent metal ion transporter

| journal = FEBS Letters

| volume = 509

| issue = 2

| pages = 309–316

|date=December 2001

| pmid = 11741608

| doi=10.1016/s0014-5793(01)03189-1

| author2-link=C. R. Allerson| author-link=H. Gunshin| doi-access=free}}

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.{{Cite journal|last1=Ma|first1=Jia|last2=Haldar|first2=Suranjana|last3=Khan|first3=Mateen A.|last4=Sharma|first4=Sohani Das|last5=Merrick|first5=William C.|last6=Theil|first6=Elizabeth C.|last7=Goss|first7=Dixie J.|date=2012-05-29|title=Fe2+ binds iron responsive element-RNA, selectively changing protein-binding affinities and regulating mRNA repression and activation|journal=Proceedings of the National Academy of Sciences|language=en|volume=109|issue=22|pages=8417–8422|doi=10.1073/pnas.1120045109|issn=0027-8424| pmc=3365203 |pmid=22586079|doi-access=free}} Several studies have identified non-canonical IREs.{{Cite journal|last1=Campillos|first1=M.|last2=Cases|first2=I.|last3=Hentze|first3=M. W.|last4=Sanchez|first4=M.|date=2010-07-01|title=SIREs: searching for iron-responsive elements|journal=Nucleic Acids Research|language=en|volume=38|issue=Web Server|pages=W360–W367|doi=10.1093/nar/gkq371|issn=0305-1048| pmc=2896125 |pmid=20460462}} It has also been shown that IRP binds to some IREs better than others.{{Cite journal|last1=Khan|first1=M. A.|last2=Ma|first2=J.|last3=Walden|first3=W. E.|last4=Merrick|first4=W. C.|last5=Theil|first5=E. C.|last6=Goss|first6=D. J.|date=2014-06-02|title=Rapid kinetics of iron responsive element (IRE) RNA/iron regulatory protein 1 and IRE-RNA/eIF4F complexes respond differently to metal ions|journal=Nucleic Acids Research|language=en|volume=42|issue=10|pages=6567–6577|doi=10.1093/nar/gku248|issn=0305-1048| pmc=4041422 |pmid=24728987}}

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).{{Cite journal

| author = T. S. Huang| author2=O. Melefors| author3-link=M. I. Lind| author3= M. I. Lind | author4-link=K. Soderhall| author4= K. Soderhall| name-list-style=amp

| title = An atypical iron-responsive element (IRE) within crayfish ferritin mRNA and an iron regulatory protein 1 (IRP1)-like protein from crayfish hepatopancreas

| journal = Insect Biochemistry and Molecular Biology

| volume = 29

| issue = 1

| pages = 1–9

|date=January 1999

| pmid = 10070739

| doi=10.1016/S0965-1748(98)00097-6

| author2-link=O. Melefors| author-link=T. S. Huang}} 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.{{Cite journal

| author = K. J. Addess| author2=J. P. Basilion| author3-link=R. D. Klausner| author3= R. D. Klausner | author4-link=T. A. Rouault| author4= T. A. Rouault | author5-link=A. Pardi| author5= A. Pardi| name-list-style=amp

| title = Structure and dynamics of the iron responsive element RNA: implications for binding of the RNA by iron regulatory binding proteins

| journal = Journal of Molecular Biology

| volume = 274

| issue = 1

| pages = 72–83

|date=November 1997

| doi = 10.1006/jmbi.1997.1377

| pmid = 9398517

| author2-link=J. P. Basilion| author-link=K. J. Addess}} 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{{Cite journal

| title = Two covariance models for iron-responsive elements

| journal = RNA Biology

| volume = 8

| issue = 5

| pages = 792–801

|date=September 2011

| pmid = 21881407

|vauthors=Stevens SG, Gardner PP, Brown C | doi = 10.4161/rna.8.5.16037

| doi-access = free

}} have been created for the IRE—one with a bulged U and one without.

Genes known to contain IREs include FTH1,{{Cite journal

| author = M. W. Hentze| author2=S. W. Caughman| author3-link=T. A. Rouault| author3= T. A. Rouault | author4-link=J. G. Barriocanal| author4= J. G. Barriocanal | author5-link=A. Dancis| author5= A. Dancis | author6-link=J. B. Harford| author6= J. B. Harford | author7-link=R. D. Klausner| author7= R. D. Klausner| name-list-style=amp

| title = Identification of the iron-responsive element for the translational regulation of human ferritin mRNA

| journal = Science

| volume = 238

| issue = 4833

| pages = 1570–1573

|date=December 1987

| pmid = 3685996

| doi=10.1126/science.3685996

| url=https://zenodo.org/record/1231213| author2-link=S. W. Caughman| author-link=M. W. Hentze}} FTL,{{Cite journal

| author = N. Aziz | author2= H. N. Munro | name-list-style=amp

| title = Iron regulates ferritin mRNA translation through a segment of its 5' untranslated region

| journal = Proceedings of the National Academy of Sciences of the United States of America

| volume = 84

| issue = 23

| pages = 8478–8482

|date=December 1987

| pmid = 3479802

| pmc=299567

| doi=10.1073/pnas.84.23.8478

| author2-link= H. N. Munro | author-link= N. Aziz | doi-access= free }} TFRC,{{Cite journal

| author = D. M. Koeller| author2= J. L. Casey| author3-link= M. W. Hentze| author3= M. W. Hentze | author4-link= E. M. Gerhardt| author4= E. M. Gerhardt | author5-link= L. N. Chan| author5= L. N. Chan | author6-link= R. D. Klausner| author6= R. D. Klausner | author7-link= J. B. Harford| author7= J. B. Harford| name-list-style=amp

| title = A cytosolic protein binds to structural elements within the iron regulatory region of the transferrin receptor mRNA

| journal = Proceedings of the National Academy of Sciences of the United States of America

| volume = 86

| issue = 10

| pages = 3574–3578

|date=May 1989

| pmid = 2498873

| pmc=287180

| doi=10.1073/pnas.86.10.3574

| author2-link= J. L. Casey| author-link= D. M. Koeller| doi-access= free}} ALAS2,{{Cite journal

| author = T. Dandekar| author2= R. Stripecke| author3-link= N. K. Gray| author3= N. K. Gray | author4-link= B. Goossen| author4= B. Goossen | author5-link= A. Constable| author5= A. Constable | author6-link= H. E. Johansson| author6= H. E. Johansson | author7-link= M. W. Hentze| author7= M. W. Hentze | name-list-style=amp

| title = Identification of a novel iron-responsive element in murine and human erythroid delta-aminolevulinic acid synthase mRNA

| journal = The EMBO Journal

| volume = 10

| issue = 7

| pages = 1903–1909

|date=July 1991

| pmid = 2050126

| pmc=452865

| doi= 10.1002/j.1460-2075.1991.tb07716.x| author2-link= R. Stripecke| author-link= T. Dandekar}} Sdhb,{{Cite journal

| author = S. A. Kohler | author2= B. R. Henderson | author3-link= L. C. Kuhn | author3=L. C. Kuhn| name-list-style=amp

| title = Succinate dehydrogenase b mRNA of Drosophila melanogaster has a functional iron-responsive element in its 5'-untranslated region

| journal = The Journal of Biological Chemistry

| volume = 270

| issue = 51

| pages = 30781–30786

|date=December 1995

| pmid = 8530520

| doi=10.1074/jbc.270.51.30781

| author2-link= B. R. Henderson | author-link= S. A. Kohler | doi-access= free

}} ACO2,{{Cite journal

| author = N. K. Gray| author2= K. Pantopoulos | author3-link= T. Dandekar | author3= T. Dandekar | author4-link= B. A. Ackrell | author4= B. A. Ackrell | author5-link= M. W. Hentze | author5= M. W. Hentze | name-list-style=amp

| title = Translational regulation of mammalian and Drosophila citric acid cycle enzymes via iron-responsive elements

| journal = Proceedings of the National Academy of Sciences of the United States of America

| volume = 93

| issue = 10

| pages = 4925–4930

|date=May 1996

| pmid = 8643505

| pmc=39381

| doi=10.1073/pnas.93.10.4925

| author2-link= K. Pantopoulos | author-link= N. K. Gray | doi-access= free }} Hao1,{{Cite journal

| author = S. A. Kohler | author2= E. Menotti | author3-link= L. C. Kuhn | author3=L. C. Kuhn | name-list-style=amp

| title = Molecular cloning of mouse glycolate oxidase. High evolutionary conservation and presence of an iron-responsive element-like sequence in the mRNA

| journal = The Journal of Biological Chemistry

| volume = 274

| issue = 4

| pages = 2401–2407

|date=January 1999

| pmid = 9891009

| doi=10.1074/jbc.274.4.2401

| author2-link= E. Menotti | author-link= S. A. Kohler | doi-access= free

}} SLC11A2 (encoding DMT1), NDUFS1,{{Cite journal

| author = E. Lin | author2= J. H. Graziano | author3-link= G. A. Freyer | author3= G. A. Freyer | name-list-style=amp

| title = Regulation of the 75-kDa subunit of mitochondrial complex I by iron

| journal = The Journal of Biological Chemistry

| volume = 276

| issue = 29

| pages = 27685–27692

|date=July 2001

| doi = 10.1074/jbc.M100941200

| pmid = 11313346

| author2-link= J. H. Graziano | author-link= E. Lin | doi-access = free

}} SLC40A1 (encoding the ferroportin){{Cite journal

| author = Athina Lymboussaki | author2= Elisa Pignatti | author3-link= Giuliana Montosi | author3= Giuliana Montosi | author4-link= Cinzia Garuti | author4= Cinzia Garuti | author5-link= David J. Haile | author5= David J. Haile | author6-link= Antonello Pietrangelo | author6= Antonello Pietrangelo | name-list-style=amp

| title = The role of the iron responsive element in the control of ferroportin1/IREG1/MTP1 gene expression

| journal = Journal of Hepatology

| volume = 39

| issue = 5

| pages = 710–715

|date=November 2003

| pmid = 14568251

| doi=10.1016/S0168-8278(03)00408-2

| author2-link= Elisa Pignatti | author-link= Athina Lymboussaki }} CDC42BPA ,{{Cite journal

| author = Radek Cmejla | author2= Jiri Petrak | author3-link= Jana Cmejlova | author3= Jana Cmejlova | name-list-style=amp

| title = A novel iron responsive element in the 3'UTR of human MRCKalpha

| journal = Biochemical and Biophysical Research Communications

| volume = 341

| issue = 1

| pages = 158–166

|date=March 2006

| doi = 10.1016/j.bbrc.2005.12.155

| pmid = 16412980

| author2-link= Jiri Petrak | author-link= Radek Cmejla }} CDC14A,{{Cite journal

| author = Mayka Sanchez | author2= Bruno Galy | author3-link= Thomas Dandekar | author3= Thomas Dandekar | author4-link= Peter Bengert | author4= Peter Bengert | author5-link= Yevhen Vainshtein | author5= Yevhen Vainshtein | author6-link= Jens Stolte | author6=Jens Stolte | author7-link= Martina U. Muckenthaler | author7= Martina U. Muckenthaler | author8-link= Matthias W. Hentze | author8= Matthias W. Hentze | name-list-style=amp

| 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

| journal = The Journal of Biological Chemistry

| volume = 281

| issue = 32

| pages = 22865–22874

|date=August 2006

| doi = 10.1074/jbc.M603876200

| pmid = 16760464

| author2-link= Bruno Galy | author-link= Mayka Sanchez | doi-access= free }} EPAS1.{{Cite journal

| author = Mayka Sanchez | author2= Bruno Galy | author3-link= Martina U. Muckenthaler | author3= Martina U. Muckenthaler | author4-link= Matthias W. Hentze | author4= Matthias W. Hentze | name-list-style=amp

| title = Iron-regulatory proteins limit hypoxia-inducible factor-2alpha expression in iron deficiency

| journal = Nature Structural & Molecular Biology

| volume = 14

| issue = 5

| pages = 420–426

|date=May 2007

| doi = 10.1038/nsmb1222

| pmid = 17417656

| s2cid= 37819604 | author2-link= Bruno Galy | author-link= Mayka Sanchez }}

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.{{Cite journal|last1=Campillos|first1=Monica|last2=Cases|first2=Ildefonso|last3=Hentze|first3=Matthias W.|last4=Sanchez|first4=Mayka|date=2010-07-01|title=SIREs: searching for iron-responsive elements|journal=Nucleic Acids Research|volume=38|issue=Web Server issue|pages=W360–W367|doi=10.1093/nar/gkq371|issn=0305-1048| pmc=2896125 |pmid=20460462}}

Taxonomic range. The IRE is found over a diverse taxonomic range—mainly eukaryotes but not in plants.{{Cite journal

| author = R. Leipuviene | author2= E. C. Theil | name-list-style=amp

| title = The family of iron responsive RNA structures regulated by changes in cellular iron and oxygen

| journal = Cellular and Molecular Life Sciences

| volume = 64

| issue = 22

| pages = 2945–2955

|date=November 2007

| doi = 10.1007/s00018-007-7198-4

| pmid = 17849083

| s2cid= 30770865 | author2-link= E. C. Theil | author-link= R. Leipuviene | pmc = 11136088

}}

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.{{Cite journal

| author = M. J. Gruer | author2= P. J. Artymiuk | author3-link= J. R. Guest | author3= J. R. Guest | name-list-style=amp

| title = The aconitase family: three structural variations on a common theme

| journal = Trends in Biochemical Sciences

| volume = 22

| issue = 1

| pages = 3–6

|date=January 1997

| pmid = 9020582

| doi=10.1016/S0968-0004(96)10069-4

| author2-link= P. J. Artymiuk | author-link= M. J. Gruer }} EPAS1 encodes a transcription factor involved in complex oxygen sensing pathways by the induction of oxygen regulated genes under low oxygen conditions.{{Cite journal

| author1 = Amar J. Majmundar | author2-link= Waihay J. Wong | author2= Waihay J. Wong | author3-link= M. Celeste Simon | author3= M. Celeste Simon

| name-list-style=amp

| title = Hypoxia-inducible factors and the response to hypoxic stress

| journal = Molecular Cell

| volume = 40

| issue = 2

| pages = 294–309

|date=October 2010

| doi = 10.1016/j.molcel.2010.09.022

| pmid = 20965423

| pmc=3143508

| author1-link= Amar J. Majmundar }} CDC42BPA encodes a kinase with a role in cytoskeletal reorganisation.{{Cite journal

| author = T. Leung | author2=X. Q. Chen| author3-link=I. Tan| author3= I. Tan| author4-link=E. Manser| author4= E. Manser | author5-link=L. Lim| author5= L. Lim| name-list-style=amp

| title = Myotonic dystrophy kinase-related Cdc42-binding kinase acts as a Cdc42 effector in promoting cytoskeletal reorganization

| journal = Molecular and Cellular Biology

| volume = 18

| issue = 1

| pages = 130–140

|date=January 1998

| pmid = 9418861

| pmc=121465

| doi=10.1128/mcb.18.1.130

| author2-link=X. Q. Chen| author-link=T. Leung}} CDC14A encodes a dual-specificity phosphatase implicated in cell cycle control{{Cite journal

| author = J. Bembenek | author2= H. Yu | name-list-style=amp

| title = Regulation of the anaphase-promoting complex by the dual specificity phosphatase human Cdc14a

| journal = The Journal of Biological Chemistry

| volume = 276

| issue = 51

| pages = 48237–48242

|date=December 2001

| doi = 10.1074/jbc.M108126200

| pmid = 11598127

| author2-link= H. Yu | author-link= J. Bembenek | doi-access = free

}} and also interacts with interphase centrosomes.{{Cite journal

| author = Niels Mailand | author2=Claudia Lukas | author3-link=Brett K. Kaiser | author3= Brett K. Kaiser | author4-link=Peter K. Jackson | author4= Peter K. Jackson | author5-link=Jiri Bartek | author5= Jiri Bartek | author6-link=Jiri Lukas | author6 = Jiri Lukas | name-list-style=amp

| title = Deregulated human Cdc14A phosphatase disrupts centrosome separation and chromosome segregation

| journal = Nature Cell Biology

| volume = 4

| issue = 4

| pages = 317–322

|date=April 2002

| doi = 10.1038/ncb777

| pmid = 11901424

| s2cid=28955777 | author2-link=Claudia Lukas | author-link=Niels Mailand }}

• 5'UTR
• IRP

{{reflist|2}}

• {{Rfam|id=RF00037|name=Iron response element - Model I}}
• {{Rfam|id=RF02253|name=Iron response element - Model II}}
• [https://web.archive.org/web/20081014045400/http://mrna.otago.ac.nz/cgi-bin/tt_data_browse/RNAMotif?PatID=T0102 Transterm page for Iron Responsive Element]
• [http://mrna.otago.ac.nz/stevens2011a/ Genomic Interval files with IRE predictions made using the RFAM models on the hg18 human genome]
• [http://ccbg.imppc.org/sires/index.html Iron Responsive Elements Prediction Server] {{Webarchive|url=https://web.archive.org/web/20120425072957/http://ccbg.imppc.org/sires/index.html |date=2012-04-25 }}

{{DEFAULTSORT:Iron Response Element}}

Category:Cis-regulatory RNA elements

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