Lecture 8 Protein Folding III

Question 1

What are the 3 quality control systems in the cells?

Answer 1

1. proteasome
2. Autophagy
3. ERAD (ER-associated Degredation)

Question 2

What are the various ways in which a protein can be folding improperly?

Answer 2

1. Improper degradation
2. Improper localization
3. dominant negative mutations
4. Gain-of-toxic function
5. Amyloid accumulation

Question 3

Describe the process of improper degradation

Answer 3

Overactive cellular degradation systems (ERAD and autophagy) can contribute to misfolding

Question 4

Describe the process of improper localization

Answer 4

For the proteins to get to the right places in the body, they must be folded correctly

If they are folded incorrectly leads to improper sub cellular localization leading to loss of function and gain of function toxicity

Question 5

Describe dominant negative mutations

Answer 5

a mutant protein antagonizes the function of the wild type protein

Question 6

What is an example of improper degredation?

Answer 6

cystic fibrosis; misfolding of the mutant proteins which are targeted for ER mediated degradation

Question 7

What is an example of improper localization?

Answer 7

Dual toxicity of AAT (alpha1- antitrypsin)

Question 8

Describe the dual toxicity of ATT in regards to the improper localization that is present.

Answer 8

ATT is supposed to be present in the lungs in order to protect the alveoli. If it is not able to escape the liver, where it is made and get to the lungs, you will have damage in your lungs including pulmonary emphysema. In addition to that, the ATT will form aggregates in the liver and lead to liver disease and damage to hepatocytes

Question 9

What are two examples of the dominant negative mutations?

Answer 9

Keratin: mutations in the keratin monomers lead to weakened filaments; which decreases the structural integrity of the cells

p53: mutant p53 is not able to bind and turn on the protective genes when stress is noted in the cell

Question 10

Describe the gain of toxic function when it comes to protein folding

Answer 10

protein conformational changes cause dominant phenotypes and the proteins become toxic to the body

Question 11

What are examples of the gain of toxic function protein folding in the body?

Answer 11

APOE4: disrupts the mitochondria and prevents the DNA helix from extending by causing strange aa binding in the cell; which can lead to peptide aggregates that are consistent with alzheimers disease

Cu/Zn superoxide dismutase: Zn atom is not properly position itself and the toxic proteins gain activity

SRC:??

Question 12

Define amyloid fibers

Answer 12

insoluble protein aggregates

Question 13

Describe amyloidogenic proteins

Answer 13

have a VQIVY sequence and can cause amyloid related diseases

some will form pore like structures that will disrupt the integrity of the cell membrane

Question 14

What are several examples of amyloid accumulation diseases?

Answer 14

Alzheimers, parkinsons, type 2 diabetes, cataracts

Question 15

Which two protein folding aggregates have a higher energy level than the native state?

Answer 15

amorphous aggregates, and amyloid fibrils

Question 16

What are the steps that lead to the formation of an amyloid plaque?

Answer 16

1. seeding/ nucleation: forms a little seed guy
2. fibril formation: recruit a bunch of lil seeds to get a fibril
3. deposit

Question 17

Who is TTR?

Answer 17

Primary carrier of the hormone thyroxine and retinol transporter; amyloidogenic

Question 18

What are two things that help to block the aggregate formation?

Answer 18

1. small molecules that act as stabilizer

2. site-specific antibodies: recognize conformational changes and sequences

Question 19

What are the keystones for environmental stressors?

Answer 19

1. detection
2. respond
3. adopt

Question 20

True or false: small levels of stress can be beneficial to an organism

Answer 20

true

Question 21

Define proteostasis

Answer 21

maintaining protein homeostasis

Question 22

What does a cell require in order maintain its functionality?

Answer 22

1. protein production
2. folding
3. degradation

Question 23

What are the complex ways to ensure proteostasis in different compartments?

Answer 23

1. cytosol (HSR)
2. ER (UPR)
3. mitochondria (UPR)

UPR= unfolded protein responses

Question 24

How are cellular proteins folded?

Answer 24

With chaperones

Question 25

Where fo membrane and secreted proteins fold and mature?

Answer 25

ER

Question 26

What is the last line of defense in regards to misfiled proteins?

Answer 26

apoptosis

Question 27

Describe UPR (ER)

Answer 27

misfolded proteins aggregate in the ER and causes a stress signal which leads to an unfolded protein response (UPR) that tries to save the cell via

1. increasing protein chaperones
2. increasing the rate of ERAD
3. Decreasing the protein production

Question 28

Describe UPR (mt)

Answer 28

encoded by nuclear and mitochondrial proteins with chaperone systems and proteases. It is able to sense the overloading of the QC system capacity and activates the transcription of nuclear encoded protective genes to re-establish homeostasis

Question 29

What are the two major chaperones that are involved in the UPRmt

Answer 29

mtHSP70 and multimedia HSP60-HSP10

Question 30

What is the first known protein misfolding disease?

Answer 30

Sickle cell anemia

Question 31

Mad cow disease, Creutzfeldt-Jakob disease, and Alzheimers disease are all caused by?

a. viruses
b. mutated mRNA
c. misfolded proteins
d. bacteria

Answer 31

C: misfolded proteins

Question 32

Which of the following occur in the unfolded protein response (UPR) that can ultimately lead to the development of type 2 diabetes?

a. General protein synthesis is activated to produce more proinsulin
b. chaperone synthesis is stimulated
c. misfolded proteins are removed from the ER and are subsequently delivered to the proteasome for destruction
d. apoptosis is triggered, leading to cell death
e. all of the above

Answer 32

E