Nuclear Receptors, Molecular Mechanisms Of Flashcards
What kind of dimers do nuclear receptors function as?
Homo- or heterodimers (similar to ECRs)
Define: homodimer
A dimer made up of 2 identical units (macromolecules) i.e. 2 of the same receptor
Define: heterodimer
A dimer made up of 2 similar but not identical units (macromolecules) i.e. 2 different types of receptor
Define: dimer
A macromolecular complex formed by 2, usually non-covalently bound, macromolecules. = a quaternary structure of a protein = now active
How are all nuclear receptors structurally related?
They all have 3 major domains
How many receptors are there in the nuclear receptor superfamily?
Genome sequencing predicts only 48 receptors
What is an orphan receptor?
The receptor is yet to have its agonist identified
Up to half of the nuclear receptor superfamily are termed orphan receptors
What can nuclear receptors also been known as?
Ligand-activated gene regulatory proteins or transcription factors
Where are nuclear receptors found in the cell?
In the cytosol or the nucleus, not associated with the lipid membrane
How many families of nuclear receptor are there?
6
How are nuclear receptors assigned a family?
Based on sequence
Name the main 3 families of nuclear receptor
1) Thyroid Receptor-like 2) Retinoid X Receptor-like 3) Oestrogen Receptor-like
How many terminals does a nuclear receptor have?
2 - N-terminal and C-terminal
What is the function of the N-terminal/domain?
Binds the agonist/ligand
What is the function of the middle domain?
DNA binding
What does the C-terminal domain contain?
Transcription-activating domain
What does the transcription-activating domain do?
The proteins will bind other transcription factors i.e. sit on top of DNA and promote or suppress transcription of DNA
Name 4 activators of nuclear receptors.
1) Steroid hormones 2) Thyroid hormones 3) Fatty acids and prostaglandins 4) The retinoids
Name 3 examples of steroid hormones.
1) Glucocorticoids e.g. cortisol 2) The steroid sex hormones (estradiol and testosterone) 3) Vitamin D
What are steroid hormones made from?
Cholesterol - a common precursor The metabolism of cholesterol = these hormones
What are thyroid hormones made from?
Tyrosine - a common precursor (an amino acid)
Name the active forms of thyroid hormones.
Thyroxine (T4) and triiodothyronine (T3)
What are fatty acids and prostaglandins derived from?
Lipids - they are the oxidation products
Name 3 examples of fatty acids and prostaglandins.
1) Prostacyclin 2) Lysophosphatidic acid 3) Leukotriene
What are retinoids synthesised from?
Vitamin A (retinol)
Name 2 examples of retinoids.
1) Retinoic acid (vitamin A acid) 2) All trans-retinoic acid
Why are all these activators of nuclear receptors poorly soluble in water?
They are small hydrophobic molecules
Specific carrier proteins bind to the activators of NRs in the blood, why?
To increase the activators’ solubility (as they must travel in the bloodstream)
What process occurs before the activators enter the cell, to do with the carrier proteins?
Dissociation
What are the main binding proteins (for transport) for the thyroid hormones?
1) Thyroxine-binding globulin 2) Transthyretin 3) Albumin
What is the major binding protein (for transport) for sex hormones?
Sex hormone-binding globulin
Which hormones does sex hormone-binding globulin bind to?
Androgens and oestrogens
What is the major steroid-binding protein called? (for transport)
Transcortin
Which steroid hormones does transcortin bind to?
Progesterone, cortisol and other corticosteroids
Explain the stages of the binding proteins transporting the hormones/activators
1) Hormones are secreted into the bloodstream from e.g. the thyroid 2) The binding protein in the bloodstream binds to the activator and transports it to the target tissue 3) The binding protein dissociates and the activator enters the tissue
Are agonists generally hydrophobic or hydrophilic?
Hydrophobic - therefore they can freely diffuse across the plasma membrane
Where do ligands bind on the nuclear receptor?
Agonists bind to the ligand-binding domain (and act as a molecular switch)
What kind of change does the ligand-binding induce in the receptor?
A conformational change
What happens to the receptor when it undergoes a conformational change?
The receptor can dimerise - become active
Where does the nuclear receptor translocate to once dimerised?
The nucleus - where the receptor has it effects, usually through gene transcription