34 - Type 2 Nuclear Receptor Flashcards
Co-regulators
o Nuclear receptors bound to HREs recruit a significant number of transcription co-regulators
o These facilitate or inhibit the transcription of tr associated target gene into mRNA
o Co-regulators are varied and include chromatin re-modelling or a bridging function to stabilise the binding of other co-regulatory proteins
What do type 2 nuclear receptors bind to?
o Type II nuclear receptors are prebound to DNA and they are interacting with corepressor proteins which maintain an inactive receptor complex
o The type II receptors tend to bind and heterodimers to the DNA, usually with the retinoic acid receptor
What happens when a hormone enters the cell?
- When a hormone enter the cell, for example thyroid hormone, it enters into the nucleus through the nuclear pore complex, interacts with the ligand binding domain of the receptor
- Causes exchange of the corepressor proteins for the coactivator proteins allowing access of RNA polymerase to the target gene
- This allows transcription and then translation to the new proteins on the ribosome
- tends to be a very slow process and there will be many target genes which are determined by the particular hormone response element for nuclear sector within their promoter regions
Where are type 2 nuclear receptors retained?
Type II receptors are retained in the nucleus bound as heterodimers (usually with RXR) to DNA
Type 2 receptors in the absence of ligand
In the absence of ligand, type II nuclear receptors are often complexed with co-repressor proteins
What does ligand binding to the nuclear receptor cause?
Ligand binding to the nuclear receptor causes dissociation of corepressor and recruitment of co-activator proteins
What are recited to the receptor?
Additional proteins, including RNA polymerase, are then recruited to the receptor/DNA complex that transcribe DNA into messenger RNA
Co-repressors
o In the absence of ligand, nuclear receptors are in a conformation that preferentially binds co-repressor proteins
o These proteins recruit histone-deacetylases (HDACs) which strengthens the association of histones to DNA thereby repressing gene transcription
Co-activators
o Binding of ligands to nuclear receptors induces a conformation of the receptor that preferentially binds co-activator proteins
o These proteins often have an intrinsic histone acetyltransferase (HAT) activity
o HATs weaken the association of histones to DNA thereby promoting gene transcription
What are histones?
Histones themselves are 8 protein subunits which wrap the DNA around them to fomr nucleosomes
o Because the DNA is tightly associated with the histones, it prevents the mRNA polymerase from accessing
What is binding of DNA to histones due to?
The binding of DNA to histones is due mainly to negative charges on the DNA interacting with positive charges on the histone
o So histones tend to be positively charged and the DNA because of its phosphodiesterase backbone is negatively charged
How can we neutralise the interaction between positive and negative charges?
We can neutralise the interaction between the positive and negative charges by acetylating the histone protein and attaching acetyl groups to them
o Loosens the DNA
Steps in the absence of a ligand
Step 1:
o In the absence of a ligand, the nuclear hormone receptor heterodimer is associated with corepressor complexes
Step 2:
o Ligand binding causes the release of the corepressor complex and the recruitment of a coactivator complex that possess histone acetyltransferase (HAT) activity that allows chromatin decompaction and gene activation
Why is HAT used?
We use HAT which are bound to the liganded nuclear receptors which causes acetylation of the histones, loosening the association and allowing DNA to unwind and the RNA polymerase access for transcription
o The acetyl groups serve as docking sites for modelling enzymes
o These ATP dependent remodelling enzymes help maintain the histones in their loose form and further allowing the polymerase to access
o the acetylation occurs on lysine residues
