(39)
9. Forklare kort hvordan translationel kontrol af genekspression kan
reguleres af RNA bindende proteiner, der påvirker messanger stabilitet og, eller
translationel initiering
Stryer, s.887-890;
fig.
31.38; fig.
31.39
Devlin, s. 1059-1060; fig.
24.3; fig. 24.4.; fig. 24.5
Modulation of the rate of transcriptional initiation is the most common mechanism of gene regulation. However, the gene expression can also be modulated at posttranscriptional level.
A typical example is the iron metabolism in humans. Iron is an essential nutrient required for the synthesis of haemoglobin and many other proteins. However, excess iron can be harmful because it can initiate a range of free-radical reactions that damage proteins, lipids and nucleic acids.
There are sophisticated systems in the cell for the accumulation of iron in times of scarcity and for the safe storage of excess iron for later use.
There are three proteins that should be considered:
Transferrin
– transport protein that carries iron absorbed in the intestines through
the serum into the liver
Transferrin receptor
– membrane protein that binds the iron loaded transferrin and initiates its
entry into the cell
Apoferritin – an iron-storing protein found in the liver and in the kidney. 24 polypeptide chains of apoferritin store 2400 iron atoms; one iron atom per aminoacid, given that a polypeptide chain consists of 100 a.a.
I will consider apoferritin first. The apoferritin mRNA has a stem-loop structure, termed the iron-responsive element in its 5’-untranslated region.
Under low iron concentrations, (when the iron should not be stored for later) the iron-responsive element is bounded by a specific protein, called aconitase, that blocks the translation of the mRNA. This means less apoferritin, and more free iron in the cells.
When the level of iron in the cell is increased, the iron binds to aconitase, which no longer can bind to the iron-responsive element on the mRNA. This means that mRNA can be translated, and new apoferritin is created that stores the excess iron.
Now to the transferrin receptor. The mRNA for the transferrin receptors has also iron-responsive elements, but they are located towards the 3’ untranslated region of the mRNA.
Under low iron concentration, aconitase binds to these iron-responsive regions, so that exonucleases can not eat the mRNA from its 3’-end before enough transferrin receptor molecule have been synthesized in order to bind more iron-loaded transferrin.
Under high iron concentration, iron binds to aconitase, so the 3’-end of mRNA is no longer protected, so that exonucleases can eat the mRNA before a lot of transferrin receptor molecules are made, so less iron is absorbed in the cell.
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