Iron response element

The Iron Response Element (IRE) is a short sequence of nucleotides found in the untranslated regions (UTRs) of certain mRNAs. These sequences play a crucial role in the post-transcriptional regulation of genes involved in iron metabolism. The IRE is recognized by specific proteins known as Iron Regulatory Proteins (IRPs), which bind to the IRE and modulate the stability and translation of the mRNA.

Structure

Structure of the Iron Response Element

The IRE is typically a stem-loop structure, consisting of a loop of nucleotides at the top and a stem formed by complementary base pairing. The loop often contains the sequence "CAGUGN" and is critical for the binding of IRPs. The stem is usually composed of five base pairs, and the bulge in the stem is important for the specific recognition by IRPs.

Function

The primary function of the IRE is to regulate the expression of genes involved in iron homeostasis. This regulation is achieved through the binding of IRPs to the IREs located in the 5' or 3' UTRs of target mRNAs.

5' UTR IREs

When an IRE is located in the 5' UTR of an mRNA, the binding of IRPs typically inhibits the translation of the mRNA. This is the case for mRNAs encoding proteins such as ferritin, which stores iron within cells. Under conditions of low iron, IRPs bind to the IREs in the 5' UTR, preventing translation and thus reducing iron storage.

3' UTR IREs

In contrast, when an IRE is located in the 3' UTR, the binding of IRPs generally stabilizes the mRNA, preventing its degradation. This is observed in mRNAs encoding the transferrin receptor, which is involved in iron uptake. Under low iron conditions, IRPs bind to the IREs in the 3' UTR, stabilizing the mRNA and increasing the production of the transferrin receptor, thereby enhancing iron uptake.

Regulation

The activity of IRPs is regulated by the cellular iron levels. Under high iron conditions, IRPs undergo a conformational change or are degraded, reducing their affinity for IREs. This allows for the translation of mRNAs with 5' UTR IREs and the degradation of mRNAs with 3' UTR IREs, thus decreasing iron uptake and increasing iron storage.

Clinical Significance

Dysregulation of IRE-IRP interactions can lead to disorders of iron metabolism. For example, mutations in the IRE of the ferritin mRNA can lead to hereditary hyperferritinemia-cataract syndrome, a condition characterized by elevated ferritin levels and early-onset cataracts.

Related Pages

• Iron Regulatory Protein
• Ferritin
• Transferrin receptor
• Iron metabolism