5 - Intro to Nuclear Receptors Flashcards
How are nuclear receptors different from cell surface receptors?
Nuclear receptors are quite different from cell surface receptors in that they have the ability to interact directly with DNA
When is a nuclear receptor in the active conformation?
When it is bound to a hormone
What does the nuclear receptor interact with?
They interact directly with groups of DNA - helical elements projecting into the DNA
What can nuclear receptors do in their active form?
They are able to regulate gene activity
What determines where on the DNA the nuclear receptor binds?
The specific base pair sequence of the DNA within the genome
What kind of hormones diffuse past the cell membrane and bind to nuclear receptors?
Small, LIPOPHILIC HORMONES diffuse past the cell membrane and bind to nuclear receptors
What does the binding of lipophilic hormones cause?
- it causes a change in the conformation of the receptor and triggers a number of events leading to up or down regulation of gene expression
- the nuclear receptors bring this about by interacting directly with the promoter, the regulatory elements of target genes
Give 3 examples of steroid hormones and what they regulate
Cortisol, oestrogen, and testosterone are steroid hormones that are synthesised from cholesterol and they regulate the stress response and sexual functions respectively
What is retinoic acid?
Retinoic acid is a derivative of vitamin A and has powerful effects on limb bud development in embryos and skin renewal in adult mammals
What is triiodothyronine?
Triiodothyronine is synthesised from tyrosine residues in the protein thyroglobulin in the thyroid gland and regulates basal metabolism
What is vitamin D?
Vitamin D is synthesised from 7-dehydrocholesterol in the skin and regulates calcium and phosphate balance in mammals
Name three steroid hormones & what they are derived from
- estradiol, testosterone, and cortisol
- all derived from the same 4 ring cholesterol core structure
How are the steroid hormones different from one another?
- there are key structural differences
- e.g., there is a hydroxyl in estradiol but not in testosterone or cortisol
- the small differences in structure allows each steroid hormone to activate a specific receptor
What are the different regions of the oestrogen receptor?
- N-terminal domain
- DNA binding domain (DBD)
- hinge region
- ligand binding domain (LBD)
- C-terminal domain
What is the general design of the nuclear receptor superfamily?
- each receptor has a HORMONE BINDING DOMAIN which binds the hormone ligand
- there is a DNA BINDING DOMAIN which interacts with DNA
- there is a VARIABLE REGION which is involved in regulating and interacting with other proteins
Conservation of DNA binding domains
- although the DNA binding domains are relatively conserved, with conservation ranging from about 42 to 94% between individual receptors
- the DNA binding domain will be different for each receptor because they interact with different sequences of DNA in the genome
Name the receptors in the nuclear receptor superfamily
- oestrogen receptor
- progesterone receptor
- glucocorticoid receptor
- thyroid hormone receptor
- retinoic acid receptor
What are the clinical effects (1) and molecular defects (2) reported to date of the androgen receptors (AR)?
A)
1. partial or complete androgen insensitivity syndrome
2. decreased receptor number, decreased androgen binding, decreased AR dimerisation
B)
1. breast cancer, prostate cancer
2. decreased AR dimerisation, AR responds to progesterone
What are the clinical effects (1) and molecular defects (2) reported to date of the glucocorticoid receptors (GR)?
- generalised inherited glucocorticoid resistance
- decreased hormone binding, decreased GR number, decreased DNA binding
What are the clinical effects (1) and molecular defects (2) reported to date of the oestrogen receptor (ER)?
- usually lethal, oestrogen resistance
- decreased hormone binding, decreased DNA binding
What are the clinical effects (1) and molecular defects (2) reported to date of the T(3) (TR) receptors?
- resistance to thyroid hormone
- TR(beta) gene defects, decreased T(3) binding
What are the clinical effects (1) and molecular defects (2) reported to date of the calcitriol (VDR) receptors?
- calcitriol-resistant rickets
- decreased VDR dimerisation
What do mutations in the nuclear receptors result in?
- each receptor is susceptible to mutations that can be inherited, and these molecular defects can lead to a number of changes to the function of the hormone receptor
- so mutations could lead to reduction in receptor binding, reductions in the ability of the receptor to interact with it’d activating hormone reduction, and the ability of an active receptor to interact with DNA and control gene transcription
What does the DNA binding domain of nuclear receptors consist of?
- helix 1 - P box
- helix 2 - D box
- helix 3 - CTE
What is the role of the P box?
- responsible to recognising the base pairs of the DNA within the genome
- discrimination of the response element (HRE)
What is the D box?
- the D box is a projected loop region, which links to the second helix
- forms a dimerisation interface
What is the role of CTE?
- critical for monomeric DNA binding
What is in helix 1 and helix 2?
- in helix 1 and helix 2 we have a coordinated zinc ion which is coordinated here by negatively charged amino acids
- the positive charge of the zinc ions is very important because it allows interaction with DNA in a really strong manner
- as the phosphodiester backbone of DNA is negatively charged, there is a strong interaction of the DNA binding domain of the receptor with the DNA
What do nuclear receptors bind to?
- receptors bind to DNA hormone response elements as heterodimers or homodimers
- steroid receptors bind as homodimers to palindromic elements spaced by three nucelotides in a symmetrical way
What can heterodimers recognise?
Heterodimers can recognise diverse HREs in which half-core motifs can be arranges as palindromes, direct repeats or inverted palindromes
What dimers are steroid hormones?
Heterodimers
What is the structure of heterodimers?
- DNA binding domain
- ligand binding domain
- and the link between them
What is the DNA formation in heterodimers?
- the DNA is formed as a palindrome
- this means the DNA binding domains line up facing each other and the ligand binding domains facing away from each other
How do heterodimers bind if interacting with palindromic DNA?
- they bind in a symmetrical fashion
How many broad classes do nuclear receptors form?
Nuclear receptors form tow broad classes according to their mechanism of action and sub cellular distribution in the absence of ligand
