III. Signal transduction and cell cycle | 37. Nuclear receptors: steroid, thyroid, retinoid and Ah receptors Flashcards

1
Q

I. Nuclear receptors
1. What are the features of Nuclear receptors?

A
  • Nuclear receptors are a class of proteins responsible for sensing steroid/thyroid hormones as well as other molecules.
  • They have the ability to directly bind to DNA and thereby regulate the expression of adjacent genes; controlling development, homeostasis or metabolism of the organism.
  • Since they can bind directly to the DNA and regulate gene expression, these nuclear receptors are classified as TFs.
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2
Q

I. Nuclear receptors
2. What is the role of nuclear receptors?

A

They have the ability to directly bind to DNA and thereby regulate the expression of adjacent genes; controlling development, homeostasis or metabolism of the organism.

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3
Q

I. Nuclear receptors
3. Why are nuclear receptors referred as TFs?

A

Since they can bind directly to the DNA and regulate gene expression, these nuclear receptors are classified as TFs.

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4
Q

I. Nuclear receptors
4. What is the consequence of binding of a ligand?

A

Binding of a ligand usually causes a conformational change in the receptor and is therefore necessary for the activation of the receptors

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5
Q

I. Nuclear receptors
5. Where are nuclear receptors found?

A

Nuclear receptors either found in the cytosol or nucleus are both referred to as nuclear receptors, since it leads to regulation of transcription in the nucleus.

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6
Q

II. Ligands
1. What are the features of ligands?

A
  • Since nuclear receptors are found inside the nucleus or cytoplasm, the ligands are small or hydrophobic enough to cross the plasma membrane.
  • Once inside, the signal molecules bind to nuclear receptor either in the cytosol or nucleus.
  • Therefore, these ligands include hydrophobic substances such as steroid hormones, thyroid hormones and so on.
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7
Q

II. Ligands
2A. What is the Structure of nuclear receptors?

A

Structure of nuclear receptors (5 DOMAINS)
1. N-terminal regulatory domain
2. DNA binding domain (DBD)
3. Hinge region
4. Ligand binding domain (LBD)
5. C-terminal domain:

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8
Q

II. Ligands
2B. Describe N-terminal regulatory domain in the Structure of nuclear receptors?

A

N-terminal regulatory domain contains the activation function 1 (AF-1), whose action is independent of the presence of the ligand

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9
Q

II. Ligands
2C. Describe DNA binding domain (DBD) in the Structure of nuclear receptors?

A

DNA binding domain (DBD) containing 2 zinc fingers that bind to specific sequences of DNA, called HRE (hormone-response-elements)

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10
Q

II. Ligands
2D. Describe Hinge region in the Structure of nuclear receptors?

A

Hinge region connects DBD + LBD, influences intracellular trafficking and subcellular distribution

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11
Q

II. Ligands
2E. Describe Ligand binding domain (LBD) in the Structure of nuclear receptors?

A
  1. LBD is an α-helical sandwich fold, where 3 antiparallel α-helices (the ‘’sandwich filling’’) are flanked by 2 α-helices on one side and 3 α-helices on the other side (the ‘’bread’’)
  2. LBD contributes to dimerization interface of the receptor + binds co-activator and co-repressor proteins
  3. Also contains the activation function 2 (AF-2), which is dependent of ligand binding
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12
Q

II. Ligands
2F. Describe C-terminal domain in the Structure of nuclear receptors?

A

Highly variable in sequence between different nuclear receptors

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13
Q

II. Ligands
3. How do we classify ligands?

A

Depending on where the nuclear receptors wait for the ligand, we can distinguish between two types:
- in the cytoplasm (type 1)
- in the nucleus (type 2)

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14
Q

II. Ligands
4A. What are the features of ligand type 1?

A
  • Anchored in the cytoplasm
  • Estrogen receptor-like
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15
Q

II. Ligands
4A. What are the features of ligand type 1?

A

Type 1 (Cytoplasm)
- Anchored in the cytoplasm
- Estrogen receptor-like

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16
Q

II. Ligands
4B. What are the 5 examples of ligand type 1?

A

Type 1 (Cytoplasm)
1. Estrogen (ER)
2. Progesterone (PR)
3. Androgens (AR)
4. Glucorticoids
5. Mineralocorticoids (MR)

17
Q

II. Ligands
5A. What are the features of Ligand Type II?

A

Type 2 (nucleus)
- Retained in the nucleus regardless of ligand binding
- Thyroid-hormone like receptor

18
Q

II. Ligands
5B. What are the 3 examples of ligand type 2?

A

Type 2 (nucleus)
- Thyroid hormone (HR)
- All-trams retinoid acid (RAR)
- Vitamin D (VDR)

19
Q

II. Ligands
1. What are the features of Steroid receptors?

A
  • Nuclear receptors that bind steroid hormones are classified as type 1 receptors
  • Steroid receptors form homodimers and bind to palindromic sequences (inverted DNA repeats).
  • They are intracellular receptors that are located within the cytoplasm of the target cell and move towards the cell nucleus upon activation by steroid hormone.
  • Belong to the nuclear receptor family of ligand-activated TFs.
20
Q

II. Ligands
2. Where can you find steroid receptors?

A

They are intracellular receptors that are located within the cytoplasm of the target cell and move towards the cell nucleus upon activation by steroid hormone.

21
Q

II. Ligands
3. Which family of receptors do steroid receptors belong to?

A

Belong to the nuclear receptor family of ligand-activated TFs.

22
Q

II. Ligands
4. What is the mechanism of steroid receptors?

A

1) At first (in the absence of ligands) the hinge region will be covered by Hsp90 (heat shock protein 90) – a type of chaperones which bind the receptor until ligand is present
2) Ligand will then enter the cell and bind to the nuclear receptor
-> dissociation of Hsp90 + activation of receptor
3) The nuclear receptor will then undergo homodimerization (2 receptor subunits join together to form 1 functional DNA-binding unit) + translocation (active transport) from cytoplasm towards the nucleus (with the help of nuclear localization signal – NLS)
4) Activated nuclear receptor binds to HRE (Hormone response elements) of DNA
5) The complex (nuclear receptor + DNA) will recruit other proteins that transcribe DNA downstream from HRE -> mRNA -> protein, which causes a change in cell function

23
Q

II. Ligands
5. What is homodimerization?

A

2 receptor subunits join together to form 1 functional DNA-binding unit

24
Q

II. Ligands
6. What is Hormone response elements (HRE)?

A

Hormone response elements (HRE): short DNA sequence within the promoter of a gene, able to bind to specific hormone receptor complexes and thereby regulate transcription.
- Specifically responds to steroid hormones.

25
Q

II. Ligands
7. What are the features of Thyroid receptors?

A

Thyroid receptors (type 2) - NUCLEUS
- Nuclear receptors that bind thyroid hormones are classified as type 2 receptors.
- Thyroid receptors form homo-/heterodimers and bind directly to DNA repeats.
- They are located inside the nucleus and do not contain any Hsp90. They are activated by binding thyroid hormone.

26
Q

II. Ligands
8. What is the mechanism of Thyroid receptors?

A

1) At first (in the absence of ligands), the nuclear receptor is already bound to the response element of DNA, but with a co-repressor protein
2) Ligands will then pass through the cell membrane + cytoplasm and enter the nucleus, where it binds to the nuclear receptor and activates it
-> dissociation of co-repressor and recruitment of co-activator proteins
3) The DNA/thyroid receptor/co-activator complex recruits RNA polymerase which transcribes DNA into mRNA and eventually a protein, resulting in a change in cell function

27
Q

II. Ligands
9. What are the features of retinoid receptors?

A

Receptor is found in the nucleus. Basically the same functions as thyroid receptors, but the ligand is retinoid.

28
Q

II. Ligands
10. What are the features of Aryl hydrocarbon receptors?

A
  • Aryl hydrocarbon receptors (type 1) - CYTOPLASM
  • The aryl hydrocarbon receptor (AhR) is a ligand-activated TF involved in regulation of biological responses.
  • These receptors are members of the family of basic helix-loop-helix (bHLH) TFs.
  • AhR has bHLH located at the N-terminal. The basic region is involved in binding of the receptor to DNA and the HLH-region which facilitates protein-protein interactions.
  • The AhR is anchored in the cytoplasm and contain Hsp90, just like type 1 nuclear receptor.
29
Q

II. Ligands
11. What do Aryl hydrocarbon receptors bind to?

A

AhR bind several exogenous ligands, such as dioxin-like compounds (carcinogenic products – smoke) and benzo[a]pyrene (halogenated aromatic hydrocarbons).

30
Q

II. Ligands
11. What do Aryl hydrocarbon receptors bind to?

A

AhR bind several exogenous ligands, such as dioxin-like compounds (carcinogenic products – smoke) and benzo[a]pyrene (halogenated aromatic hydrocarbons).

31
Q

II. Ligands
12. What is the mechanism of Aryl hydrocarbon receptors?

A

1) At first (in absence of ligands), AhR will be inactive and bound to Hsp90
2) Ligands (aromatic chemicals) enter the cell and bind to AhR -> dissociation of Hsp90 + activation of receptor
3) The AhR will then undergo translocation the nucleus + dimerization with ARNT (AhR nuclear translocator) -> changes in gene transcription
4) Binds to response element of DNA -> induces transcription (ex: of enzymes/molecules needed for proper functions of cells)

32
Q

II. Ligands
13. What is the significance of Aryl hydrocarbon receptors (type 1) - CYTOPLASM?

A
  • The AhR have been shown to regulate xenobiotic-metabolizing enzymes.
  • Xenobiotics are biologically active, foreign chemical substances that are not naturally produced by or normally expected to be present in the organism (medicines, poisons, pollutants).
  • XRE, the response element in DNA that binds AhR, is responsible for metabolism of xenobiotics.