Nuclear and Apoptotic Receptors

Question 1

How do nuclear receptors promote a biological effect?

Answer 1

By regulating transcription.

Question 2

Where are steroid receptors present in the cell? What about thyroid hormone receptors?

Answer 2

Glucocorticoid: cytoplasm
Thryroid: nucleus

Question 3

What 4 types of receptors make up the steroid receptor family?

Answer 3

1. Glucocorticoid receptor
2. Mineralocorticoid receptor
3. Androgen receptor
4. Progesterone receptor

Question 4

What 6 types of receptors make up the thyroid receptor family?

Answer 4

1. Thyroid hormone receptor
2. Estrogen receptor
3. Retinoic acid receptor
4. Retinoic X receptor
5. Peroxisome proliferator-activated receptor
6. Vitamin D receptor

Question 5

Which known steroid has a receptor which is part of the thyroid receptor family, rather than the steroid receptor family? Why?

Answer 5

Estrogen, because of receptor structural homology.

Question 6

Are nuclear receptors soluble?

Answer 6

Yes, they are not membrane bound and can move about freely.

Question 7

Besides steroid receptors and thyroid hormone receptors, what other category of receptors are there? What defines these?

Answer 7

“Orphan receptors” which have no known ligand.

Question 8

What differentiates the ligands for nuclear receptors from the ligands of other receptors?

Answer 8

Nuclear receptor ligands are not proteins, but rather small hydrophobic molecules that diffuse across membranes.

Question 9

What are the 3 domains which make up a nuclear receptor?

Answer 9

1. Amino terminal domain
2. DNA binding domain
3. Ligand binding domain

Question 10

What is the function of the nuclear receptor’s amino terminal domain?

Answer 10

Ligand-independent transactivation.

Question 11

What are the functions of the nuclear receptor’s DNA binding domain? What characteristic structure is present here?

Answer 11

DNA binding and dimerization. The zinc fingers here make it possible for DNA to bind.

Question 12

What are the functions of the nuclear receptor’s ligand binding domain?

Answer 12

Ligand binding, ligand-dependent transactivation. Also responsible for hetero/homo-dimerization as well as association with heat shock proteins and nuclear translocation.

Question 13

What do mutations in the nuclear (thyroid) receptor’s ligand binding domain often cause?

Answer 13

Diseases from resistance to thyroid hormone (attention deficit to severe brain disorders)

Question 14

What is the purpose of the AF-1 subdomain in nuclear receptors?

Answer 14

Alters the conformation of the receptor, changing ligand binding.

Question 15

Do nuclear receptor ligands always bind to their receptors?

Answer 15

No, they can act alone and have non-genomic effects (thyroid hormone, steroid hormones)

Question 16

What is the purpose of the “zinc finger” motif? How do they accomplish this?

Answer 16

Generally a pair of zinc fingers on the nuclear receptor. The first binds DNA while the second is involved in dimerization of the receptor.

Question 17

What structure do steroid receptors assume upon ligand-binding? What thyroid hormone receptor mimics this? How are their recognition sequences arranged?

Answer 17

They bind as homodimers. Estrogen receptors also assume this conformation. Recognition sequences are palindrome/inverted repeats (ex: AGANNNTGT).

Question 18

What structure do thyroid receptors assume upon ligand-binding? How are their recognition sequences arranged?

Answer 18

They bind as heterodimers (prefer 1 TR and 1 RXR). Recognition sequences are direct repeats (ex: TCANNNTCA) or palindrome/inverted repeats (ex: AGANNNTGT).

Question 19

What is meant by the “mousetrap” in a nuclear hormone receptor? What does this structure do?

Answer 19

A phobic pocket in the receptor (12a-helices + 1b-turn) which can bind antagonists or agonists to control coactivator binding.

Question 20

What 3 steps describe the corepression/coactivation of nuclear receptors?

Answer 20

1. A repressor complex with histone deacetylases close chromatin
2. While transcription is repressed, ligand binds and remodels chromatin (uses ATP)
3. histone acetyltransferases reopen chromatin

Question 21

What differentiates nuclear receptors from membrane receptors when comparing against blood binding protein?

Answer 21

The association with a membrane. Every other characteristic of receptors compared to blood binding protein still holds (specificity, affinity, saturability, etc).

Question 22

What differentiates the roles of histone deacetylases (HDACs) from histone acetyltransferases (HATs)?

Answer 22

HDAC: closes chromatin, repressing transcription.
HAT: opens chromatin, activating transcription.

Question 23

What are some examples of molecules which help promote cell proliferation?

Answer 23

Estrogen, testosterone, epidermal growth hormone, etc.

Question 24

What differentiates an extracellular apoptotic signal from an intracellular apoptotic signal?

Answer 24

Extracellular: increased receptor expression on membrane signals the need for death to nearby cells
Intracellular: initiated at mitochondria (maybe by detecting shortening telomeres)

Question 25

In which process is FAS receptor involved? How does it differ from other receptors which we’ve discussed?

Answer 25

Apoptotic response (specifically extracellular signal). FAS receptors are trimeric rather than dimeric (as the other receptors are).

Question 26

Why don’t apoptotic cells simply lyse and spill their contents into the extracellular space?

Answer 26

Because this could trigger an immune response, causing additional harm.

Question 27

Describe the 4 steps which lead to intracellularly stimulated apoptosis.

Answer 27

1. Mitochondria detects stimuli, releases cytochrome c
2. Cytochrome c transduces initiator caspase signalling (Cas-9)
3. Initiator caspase signals effector caspase
4. Effector caspase triggers degredation of structure (apoptosis)

Question 28

Describe the 3 steps which lead to extracellularly stimulated apoptosis.

Answer 28

1. FAS receptors on membrane receive apoptotic stimuli
2. The FASr death domain associates with a caspace, stimulating an initiator caspace (Cas-8)
3. Initiator either signals an effector caspase or the mitochondria to trigger apoptosis

Question 29

What molecules are responsible for providing apoptotic stimuli to the mitochondria in response to extracellular apoptotic signalling?

Answer 29

Pro-apoptotic Bcl-2 (family) regulators

Question 30

What effect does tamoxifen have on the estrogen receptor?

Answer 30

It acts as an antagonist.