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SMP - MNE Exam 1 > Lecture 8: Hormone Receptors > Flashcards

Lecture 8: Hormone Receptors Flashcards

1
Q

What are the 7 domains of a nuclear hormone receptor?

A
  1. Hormone binding
  2. DNA binding
  3. Nuclear localization
  4. Dimerization/Modulation/Phosphorylation domains
  5. Transducing domain
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2
Q

What are the 6 domains of a membrane hormone receptor? Which ones are in the cell and which ones are out?

A
  1. Hormone binding (out)
  2. Transmembrane (within)
  3. Dimerization (out)
  4. Modulation (in)
  5. Phosphorylation (in)
  6. Transducing domain (in)
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3
Q

What are the 4 ways for a membrane hormone receptor to trigger a second messenger system?

A
  1. Dimerization
  2. Modulation
  3. Phosphorylation domains
  4. Enzymatic activity
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4
Q

What method is used by membrane receptors to induce a conformational change leading to transduction of response/second messenger cascade?

A

Dimerization

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5
Q

Which is inside the cell: N or C terminus of membrane hormone receptor?

A

Depends!

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6
Q

Where is the hormone-binding domain of nuclear hormone receptors? What is particular about it?

A

At the C-terminal

LARGE: ~250 AAs

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7
Q

What is the function of the nuclear localization domain of the nuclear hormone receptor?

A

Allows receptor to localize the nucleus of the cell

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8
Q

When does the nuclear hormone receptor enter the nucleus?

A

Could have always been there or upon binding to the hormone in the cytosol

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9
Q

What is the transducing domain of the nuclear hormone receptor?

A

Could be considered the entire hormone receptor

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10
Q

What is an agonist?

A

Molecule that binds to the hormone receptor and brings about a response

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11
Q

What is an antagonist?

A

Molecule that binds to the hormone receptor and inhibits the agonist responses

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12
Q

What is the role of the transducing domain of the membrane hormone receptor? What part of the receptor is it?

A

To induce second messengers

Cytoplasmic side of the receptor

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13
Q

What is the role of the transducing domain of the nuclear hormone receptor?

A

Activate transcription

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14
Q

Which bind better: agonists or antigonists?

A

Agonists usually

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15
Q

How can one determine if the binding domain of a hormone receptor binds the hormone reversibly?

A

Binding assay: scatchard plots

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16
Q

Which type of receptors can be glycosylated?

A

Membrane receptors

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17
Q

Which type of membrane receptors can have enzymatic activity??

A

Membrane receptors

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18
Q

What is an example of a partial/weak antagonist?

A

Ru486: works to inhibit progesterone receptor but partially inhibits the glucocorticoid receptor

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19
Q

What can an antagonist’s properties depend on? Example?

A

The tissue it is in!

Eg: tamoxifen inhibits estradiol receptors well in breasts and poorly in bone

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20
Q

What does hGR stand for?

A

Glucocorticoid receptor

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21
Q

What does hMR stand for?

A

Mineralcorticoid receptor

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22
Q

What does hAR stand for?

A

Androgen receptor

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23
Q

What does hPR stand for?

A

Progesterone receptor

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24
Q

What does hERalpha and B stand for?

A

Alpha and beta estrogen receptors

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25
Q

What does hTR stand for?

A

Thyroid receptor

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26
Q

What are the 2 main types of hTRs?

A

Alpha 1 and beta 1

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27
Q

What does hRAR stand for?

A

Retinoic acid receptor

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28
Q

What are the 3 types of hRARs?

A

Alpha, beta, gamma

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29
Q

What does hRXR stand for?

A

Retinoic acid X receptor

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30
Q

What are the 3 types of hRXRs?

A

Alpha, beta, gamma

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31
Q

What does hPPAR stand for?

A

Perioxosime proliferator

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32
Q

What do hPPARs regulate?

A

Lipid metabolism

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33
Q

What are the 3 types of hPPARs?

A

Alpha, beta, gamma

34
Q

What does hVDR stand for?

A

Vitamin D receptor

35
Q

What are the 3 groupings of nuclear receptors? What do they each share?

A
  1. Steroid receptors: hGR, hMR, hAR, hPR
  2. Estrogen receptors: hER alpha and beta
  3. Others: hTR (alpha 1 and beta 1), hRAR alpha, hRXR alpha, hPPAR alpha, hVDR

They share P-box sequences

36
Q

What % range AA homology between the hormone binding domains of nuclear receptors? But…?

A

15-50%

But conserved structure between all of them.

37
Q

Describe the common structure of hormone binding domains of nuclear receptors? How come they all have it?

A

11-12 alpha helices arranged like a 3 layer sandwich with a hydrophobic hole/pocket
Helix 12 is the last helix at the C-terminus with 2 surfaces and is separate from the sandwich: hydrophobic (toward hormone) and hydrophilic –> the hydrophilic one interacts with coactivator proteins to regulate transcription

Evolution!

38
Q

Describe the mechanism by which nuclear receptors bind hormones.

A
  1. Hormone binds and causes all of the helices to crunch together: huge conformational change = induced fit
  2. Helix 12 seals the binding cavity and exposes its hydrophilic surface to regulate transcription
39
Q

What is the N terminal of nuclear hormone receptors often involved with?

A

Transcriptional activation and nuclear localization

40
Q

Describe the structure of the DNA binding domain of nuclear hormone receptors. Where is it located?

A

2 zinc fingers + 2 alpha helices in a globular structure

Located in the center of the molecule

41
Q

What part of the DNA binding domain of nuclear hormone receptors interacts with the DNA? 3 names

A

The first zinc finger = P-box = recognition helix

42
Q

How would changing the P-box sequence affect binding of nuclear hormone receptor to DNA?

A

Would change the binding specificity

43
Q

Can the hormones activating the nuclear receptors that have the same P-box activate all of them?

A

NOPE, more complicated than that BUT they could bind to the same DNA binding site

44
Q

How do ALL hormones bind to nuclear receptors?

A

As DIMERS to DOUBLE-STRANDED DNA

45
Q

What DNA sequence do steroid receptors bind?

A

Palindrome sequence separated by any 3 nucleotides

46
Q

What DNA sequence do estrogen receptors bind?

A

Palindrome sequence separated by any 3 nucleotides

47
Q

What 2 DNA sequences do thyroid receptors bind?

A
  1. Palindrome sequence not separated by nucleotides

2. Direct repeats separated by any 4 nucleotides

48
Q

What DNA sequence do VDRs bind?

A

Direct repeat separated by any 3 nucleotides

49
Q

What DNA sequence do RARs bind?

A

Direct repeat separated by any 5 nucleotides

50
Q

Which DNA sequences bind nuclear hormone receptors more tightly and with high affitiny: direct repeats or palindromes?

A

Palindromes

51
Q

How is steroid receptor binding to DNA regulated?

A

Heat Shock Proteins are bound to the hormone binding domain of the receptor and are released upon hormone binding

52
Q

What is the main Heat Shock Protein used to regulate steroid receptor binding to DNA?

A

HSP90

53
Q

What is the receptor binding site sequence of the transcriptional coactivators?

A

LLxxLL
L: leucine
x: any AA

54
Q

Do TRs need hormones to bind DNA?

A

Not necessarily

55
Q

How is thyroid receptor activation of DNA transcription regulated?

A

Suppressor proteins that are released upon hormone binding due to a conformational change and coactivators bind

56
Q

What molecules can bind hPPARs?

A

Arachidonic acid metabolites

57
Q

What molecules bind hRARs?

A

All-trans retinoic acids

58
Q

What molecules bind hRXRs?

A

9-cis retinoic acid

59
Q

What is the main role of hRXRs? With which receptors?

A

Form heterodimers with other nuclear receptors

All except for steroid receptors: PPAR, RAR, TR, and VDR

60
Q

What does the dissociation constant of a hormone correspond to?

A

The concentration of hormone that half saturates the receptor

61
Q

What is equation to calculation the amount of hormone bound to a receptor?

A

Hormone bound = Max . [hormone] / Kd + [hormone]

Max = maximum possible hormone binding

62
Q

When is regulation of the hormone binding to the receptor most powerful?

A

Around the Kd of that hormone

63
Q

What is the purpose of a Stachard plot?

A

To find Kd

64
Q

What are the 2 points to know on a Stachard plot?

A
  1. Slope = -1/Kd

2. x-intercept = # of binding sites (or receptors if only 1 binding site per receptor)

65
Q

What does a steeper slope on a Stachard plot mean?

A

Tighter binding

66
Q

What does a curve instead of a line on a Stachard plot mean?

A

Concentration is very far from the Kd OR receptors with different affinities to a hormone

67
Q

Which receptor is used for comparison to all the others?

A

hGR

68
Q

What allows the common structure of the hormone binding domain of nuclear receptors to bind different hormones?

A

The induced fit nature of it

69
Q

Describe the specificity of the DNA binding domain of nuclear receptors.

A

Low DNA binding specificity (only 66 amino acids in this region). But the P box forms alpha helices that will enter the major grooves of DNA. Some of these alpha helices are important for specificity

70
Q

How do most transcription factors interact with DNA?

A

By entering the major grooves

71
Q

Which nuclear receptors can bind DNA as homodimers very EASILY?

A

Those that have palindromic DNA binding sequences: GR, MR, PR, AR, ER (all the steroid receptors), TR

72
Q

What is the direct repeat DNA binding sequence used for in nuclear receptors?

A

Hetero OR homodimers

73
Q

Why do different nuclear receptors have different spacing between their DNA binding sequences?

A

To make room for the different nuclear receptor

74
Q

Why is it very easy to get mutations in the androgen receptor?

A

Because it’s X-linked

75
Q

What is the Type 1 GR?

A

MR

76
Q

What is the Type 2 GR?

A

GR

77
Q

Type 2 diabetes drugs that increase the sensitivity to insulin target which type of nuclear receptors?

A

PPAR gamma

78
Q

What are the 2 axis of a Statchard plot?

A
  1. x-axis: bound

2. y-axis: bound/free

79
Q

What are the 2 axis of a hormone binding curve? What shift shows tighter binding?

A
  1. x-axis: log [hormone]
  2. y-axis: relative binding

LEFT SHIFT

80
Q

What domain of the nuclear receptor determines what subclass the receptor belongs to?

A

DNA binding domain

81
Q

What is the role of the 2 zinc fingers? Do they interact with the DNA?

A

To situate the P box in the right major groove of DNA

They do not interact with the DNA

SMP - MNE Exam 1 (25 decks)

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