In
molecular biology
Molecular biology is the branch of biology that seeks to understand the molecular basis of biological activity in and between cells, including biomolecular synthesis, modification, mechanisms, and interactions. The study of chemical and physi ...
, the iron response element or iron-responsive element (IRE) is a short conserved
stem-loop
Stem-loop intramolecular base pairing is a pattern that can occur in single-stranded RNA. The structure is also known as a hairpin or hairpin loop. It occurs when two regions of the same strand, usually complementary in nucleotide sequence when ...
which is bound by
iron response proteins (IRPs, also named IRE-BP or IRBP). The IRE is found in
UTRs (untranslated regions) of various
mRNA
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 Protein biosynthesis, synthesizing a protein.
mRNA is ...
s whose products are involved in
iron metabolism
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 impo ...
. For example, the mRNA of
ferritin
Ferritin is a universal intracellular protein that stores iron and releases it in a controlled fashion. The protein is produced by almost all living organisms, including archaea, bacteria, algae, higher plants, and animals. It is the primary ' ...
(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
Transferrin receptor (TfR) is a carrier protein for transferrin. It is needed for the import of iron into the cell and is regulated in response to intracellular iron concentration. It imports iron by internalizing the transferrin-iron complex thro ...
(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
Fe-4Sand adopts an aconitase conformation unsuitable for IRE binding. In contrast, IRP2 is degraded in high iron conditions. There is variation in affinity between different IREs and different IRPs.
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. Several studies have identified non-canonical IREs. It has also been shown that IRP binds to some IREs better than others.
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). 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. 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 have been created for the IRE—one with a bulged U and one without.
Genes with IREs
Genes known to contain IREs include
FTH1
Ferritin heavy chain is a ferroxidase enzyme that in humans is encoded by the ''FTH1'' gene. FTH1 gene is located on chromosome 11, and its mutation causes Hemochromatosis type 5.
Function
This gene encodes the heavy subunit of ferritin, the m ...
,
FTL,
TFRC
Transferrin receptor protein 1 (TfR1), also known as Cluster of Differentiation 71 (CD71), is a protein that in humans is encoded by the ''TFRC'' gene. TfR1 is required for iron import from transferrin into cells by endocytosis.
Structure and fun ...
,
ALAS2
Delta-aminolevulinate synthase 2 also known as ALAS2 is a protein that in humans is encoded by the ''ALAS2'' gene. ALAS2 is an aminolevulinic acid synthase.
The product of this gene specifies an erythroid-specific mitochondrially located enzyme ...
, Sdhb,
ACO2
Aconitase 2, mitochondrial is a protein that in humans is encoded by the ACO2 gene.
Structure
The secondary structure of ACO2 consists of numerous alternating alpha helices and beta sheets (SCOP classification: α/β alternating). The tertiary st ...
, Hao1,
SLC11A2
Natural resistance-associated macrophage protein 2 (NRAMP 2), also known as divalent metal transporter 1 (DMT1) and divalent cation transporter 1 (DCT1), is a protein that in humans is encoded by the ''SLC11A2'' (solute carrier family 11, member 2) ...
(encoding DMT1),
NDUFS1,
SLC40A1
Ferroportin-1, also known as solute carrier family 40 member 1 (SLC40A1) or iron-regulated transporter 1 (IREG1), is a protein that in humans is encoded by the ''SLC40A1'' gene, and is part of the Ferroportin (Fpn) FamilyTC# 2.A.100. Ferroportin i ...
(encoding the ferroportin)
CDC42BPA
Serine/threonine-protein kinase MRCK alpha is an enzyme that in humans is encoded by the ''CDC42BPA'' gene.
The protein encoded by this gene is a member of the Serine/Threonine protein kinase family. This kinase contains multiple functional domai ...
,
CDC14A,
EPAS1
Endothelial PAS domain-containing protein 1 (EPAS1, also known as hypoxia-inducible factor-2alpha (HIF-2α)) is a protein that is encoded by the ''EPAS1'' gene in mammals. It is a type of hypoxia-inducible factor, a group of transcription factor ...
.
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.
Taxonomic range. The IRE is found over a diverse taxonomic range—mainly eukaryotes but not in plants.
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
Isocitric acid is a structural isomer of citric acid. Since citric acid and isocitric acid are structural isomers, they share similar physical and chemical properties. Due to these similar properties, it is difficult to separate the isomers. Salt ...
. EPAS1 encodes a
transcription factor
In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The fu ...
involved in complex oxygen sensing pathways by the induction of oxygen regulated genes under low oxygen conditions. CDC42BPA encodes a
kinase
In biochemistry, a kinase () is an enzyme that catalyzes the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates. This process is known as phosphorylation, where the high-energy ATP molecule don ...
with a role in cytoskeletal reorganisation. CDC14A encodes a dual-specificity phosphatase implicated in cell cycle control and also interacts with interphase centrosomes.
See also
*
5'UTR
*
IRP
References
External links
*
*
Transterm page for Iron Responsive ElementGenomic Interval files with IRE predictions made using the RFAM models on the hg18 human genome
{{DEFAULTSORT:Iron Response Element
Cis-regulatory RNA elements
Articles containing video clips