Lecture 8 Protein Folding III Flashcards
What are the 3 quality control systems in the cells?
- proteasome
- Autophagy
- ERAD (ER-associated Degredation)
What are the various ways in which a protein can be folding improperly?
- Improper degradation
- Improper localization
- dominant negative mutations
- Gain-of-toxic function
- Amyloid accumulation
Describe the process of improper degradation
Overactive cellular degradation systems (ERAD and autophagy) can contribute to misfolding
Describe the process of improper localization
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
Describe dominant negative mutations
a mutant protein antagonizes the function of the wild type protein
What is an example of improper degredation?
cystic fibrosis; misfolding of the mutant proteins which are targeted for ER mediated degradation
What is an example of improper localization?
Dual toxicity of AAT (alpha1- antitrypsin)
Describe the dual toxicity of ATT in regards to the improper localization that is present.
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
What are two examples of the dominant negative mutations?
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
Describe the gain of toxic function when it comes to protein folding
protein conformational changes cause dominant phenotypes and the proteins become toxic to the body
What are examples of the gain of toxic function protein folding in the body?
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:??
Define amyloid fibers
insoluble protein aggregates
Describe amyloidogenic proteins
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
What are several examples of amyloid accumulation diseases?
Alzheimers, parkinsons, type 2 diabetes, cataracts
Which two protein folding aggregates have a higher energy level than the native state?
amorphous aggregates, and amyloid fibrils
What are the steps that lead to the formation of an amyloid plaque?
- seeding/ nucleation: forms a little seed guy
- fibril formation: recruit a bunch of lil seeds to get a fibril
- deposit
Who is TTR?
Primary carrier of the hormone thyroxine and retinol transporter; amyloidogenic
What are two things that help to block the aggregate formation?
- small molecules that act as stabilizer
2. site-specific antibodies: recognize conformational changes and sequences
What are the keystones for environmental stressors?
- detection
- respond
- adopt
True or false: small levels of stress can be beneficial to an organism
true
Define proteostasis
maintaining protein homeostasis
What does a cell require in order maintain its functionality?
- protein production
- folding
- degradation
What are the complex ways to ensure proteostasis in different compartments?
- cytosol (HSR)
- ER (UPR)
- mitochondria (UPR)
UPR= unfolded protein responses
How are cellular proteins folded?
With chaperones
Where fo membrane and secreted proteins fold and mature?
ER
What is the last line of defense in regards to misfiled proteins?
apoptosis
Describe UPR (ER)
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
- increasing protein chaperones
- increasing the rate of ERAD
- Decreasing the protein production
Describe UPR (mt)
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
What are the two major chaperones that are involved in the UPRmt
mtHSP70 and multimedia HSP60-HSP10
What is the first known protein misfolding disease?
Sickle cell anemia
Mad cow disease, Creutzfeldt-Jakob disease, and Alzheimers disease are all caused by?
a. viruses
b. mutated mRNA
c. misfolded proteins
d. bacteria
C: misfolded proteins
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
E
