Iron-responsive Element-binding Protein - Iron Transport

Iron Transport

All cells use some iron, and must get it from the circulating blood. Since iron is tightly bound to transferrin, cells throughout the body have receptors for transferrin-iron complexes on their surfaces. These receptors engulf and internalize both the protein and the iron attached to it. Once inside, the cell transfers the iron to ferritin, the internal iron storage molecule.

Cells have advanced mechanisms for sensing their own need for iron. In human cells, the best-characterized iron-sensing mechanism is the result of post-transcriptional regulation of mRNA (the chemical instructions derived from DNA genes to make proteins). Sequences of mRNA called iron-responsive elements (IREs) are contained within the mRNA sequences that code for transferrin receptors and for ferritin. Iron-responsive element-binding protein (IRE-BP) binds to these mRNA sequences. On its own, the IRE-BP binds to the IREs of ferritin and transferrin receptor mRNA. But, when iron binds to the IRE-BP, the IRE-BP changes shape with the result that the IRE-BPs can no longer bind the ferritin mRNA. This liberates the mRNA to direct the cell to make more ferritin. In other words, when there is high iron in the cell, the iron itself causes the cell to produce more iron storage molecules. (The IRE-BP is an aconitase; for a schematic drawing of the shape change, see here).

Transferrin receptor production depends on a similar mechanism. But this one has the opposite trigger, and the opposite ultimate effect. IRE-BPs without iron bind to the IREs on transferrin receptor mRNA. But those IREs have a different effect: When the IRE-BP binds to these sites, the binding not only allows for translation but also stabilizes the mRNA molecule so it can stay intact for longer.

In low-iron conditions, IRE-BPs allow the cell to keep producing transferrin receptors. And more transferrin receptors make it easier for the cell to bring in more iron from transferrin-iron complexes circulating outside the cell. But, as iron binds to more and more IRE-BPs, they change shape and unbind the transferrin receptor mRNA. The transferrin receptor mRNA is rapidly degraded without the IRE-BP attached to it. The cell stops producing transferrin receptors.

When the cell has obtained more iron than it can bind up with ferritin or heme molecules, more and more iron will bind to the IRE-BPs. That will stop transferrin receptor production. And iron-IRE-BP binding will also start ferritin production.

When the cell is low on iron, less and less iron will bind to IRE-BPs. The IRE-BPs without iron will bind to transferrin receptor mRNA.