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A10CB > 5 - Intro to Nuclear Receptors > Flashcards

5 - Intro to Nuclear Receptors Flashcards

1
Q

How are nuclear receptors different from cell surface receptors?

A

Nuclear receptors are quite different from cell surface receptors in that they have the ability to interact directly with DNA

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2
Q

When is a nuclear receptor in the active conformation?

A

When it is bound to a hormone

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3
Q

What does the nuclear receptor interact with?

A

They interact directly with groups of DNA - helical elements projecting into the DNA

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4
Q

What can nuclear receptors do in their active form?

A

They are able to regulate gene activity

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5
Q

What determines where on the DNA the nuclear receptor binds?

A

The specific base pair sequence of the DNA within the genome

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6
Q

What kind of hormones diffuse past the cell membrane and bind to nuclear receptors?

A

Small, LIPOPHILIC HORMONES diffuse past the cell membrane and bind to nuclear receptors

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7
Q

What does the binding of lipophilic hormones cause?

A
  • 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
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8
Q

Give 3 examples of steroid hormones and what they regulate

A

Cortisol, oestrogen, and testosterone are steroid hormones that are synthesised from cholesterol and they regulate the stress response and sexual functions respectively

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9
Q

What is retinoic acid?

A

Retinoic acid is a derivative of vitamin A and has powerful effects on limb bud development in embryos and skin renewal in adult mammals

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10
Q

What is triiodothyronine?

A

Triiodothyronine is synthesised from tyrosine residues in the protein thyroglobulin in the thyroid gland and regulates basal metabolism

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11
Q

What is vitamin D?

A

Vitamin D is synthesised from 7-dehydrocholesterol in the skin and regulates calcium and phosphate balance in mammals

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12
Q

Name three steroid hormones & what they are derived from

A
  • estradiol, testosterone, and cortisol
  • all derived from the same 4 ring cholesterol core structure
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13
Q

How are the steroid hormones different from one another?

A
  • 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
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14
Q

What are the different regions of the oestrogen receptor?

A
  1. N-terminal domain
  2. DNA binding domain (DBD)
  3. hinge region
  4. ligand binding domain (LBD)
  5. C-terminal domain
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15
Q

What is the general design of the nuclear receptor superfamily?

A
  • 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
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16
Q

Conservation of DNA binding domains

A
  • 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
17
Q

Name the receptors in the nuclear receptor superfamily

A
  1. oestrogen receptor
  2. progesterone receptor
  3. glucocorticoid receptor
  4. thyroid hormone receptor
  5. retinoic acid receptor
18
Q

What are the clinical effects (1) and molecular defects (2) reported to date of the androgen receptors (AR)?

A

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

19
Q

What are the clinical effects (1) and molecular defects (2) reported to date of the glucocorticoid receptors (GR)?

A
  1. generalised inherited glucocorticoid resistance
  2. decreased hormone binding, decreased GR number, decreased DNA binding
20
Q

What are the clinical effects (1) and molecular defects (2) reported to date of the oestrogen receptor (ER)?

A
  1. usually lethal, oestrogen resistance
  2. decreased hormone binding, decreased DNA binding
21
Q

What are the clinical effects (1) and molecular defects (2) reported to date of the T(3) (TR) receptors?

A
  1. resistance to thyroid hormone
  2. TR(beta) gene defects, decreased T(3) binding
22
Q

What are the clinical effects (1) and molecular defects (2) reported to date of the calcitriol (VDR) receptors?

A
  1. calcitriol-resistant rickets
  2. decreased VDR dimerisation
23
Q

What do mutations in the nuclear receptors result in?

A
  • 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
24
Q

What does the DNA binding domain of nuclear receptors consist of?

A
  1. helix 1 - P box
  2. helix 2 - D box
  3. helix 3 - CTE
25
Q

What is the role of the P box?

A
  • responsible to recognising the base pairs of the DNA within the genome
  • discrimination of the response element (HRE)
26
Q

What is the D box?

A
  • the D box is a projected loop region, which links to the second helix
  • forms a dimerisation interface
27
Q

What is the role of CTE?

A
  • critical for monomeric DNA binding
28
Q

What is in helix 1 and helix 2?

A
  • 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
29
Q

What do nuclear receptors bind to?

A
  • 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
30
Q

What can heterodimers recognise?

A

Heterodimers can recognise diverse HREs in which half-core motifs can be arranges as palindromes, direct repeats or inverted palindromes

31
Q

What dimers are steroid hormones?

A

Heterodimers

32
Q

What is the structure of heterodimers?

A
  • DNA binding domain
  • ligand binding domain
  • and the link between them
33
Q

What is the DNA formation in heterodimers?

A
  • 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
34
Q

How do heterodimers bind if interacting with palindromic DNA?

A
  • they bind in a symmetrical fashion
35
Q

How many broad classes do nuclear receptors form?

A

Nuclear receptors form tow broad classes according to their mechanism of action and sub cellular distribution in the absence of ligand

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