Lecture 8 - Protein Folding III (Protein Folding Disorders)

Question 1

By what mechanisms can protein misfolding lead to disease?

L8 S5

Answer 1

• improper degradation
• improper localization
• dominant negative mutations
• gain-of-toxic function
• amyloid accumulation

Question 2

What was the first know protein-misfolding disease?

L8

A. Alzheimer’s disease
B. ALS
C. Sickle cell anemia
D. Parkinson’s disease
E. Cystic fibrosis

Answer 2

C. Sickle cell anemia

Question 3

How can protein-misfolding lead to improper degradation and disease?
What is an example of a disease caused by this?

L8 S6

Answer 3

A misfolded protein can be targeted for degradation which will result in loss of function as the protein is destroyed.

An example of this is cystic fibrosis in which there is an accumulation of a misfolded chloride ion channel in the ER membrane instead of in the cell membrane because it was targeted for degradation.

Question 4

How can protein-misfolding lead to improper localization and disease?
What is an example of a disease caused by this?

L8 S7

Answer 4

If a protein is misfolded its localization signal may be hidden or it might not be able to be transported/inserted into its final destination. This can result in the protein carrying out its function in the wrong location.

An example of this is AAT (α1-antitrypsin) deficiency. The protein is produced in the liver and transported to the lungs but if it is misfolded it remains in the liver and the function in the lungs does not occur.

Question 5

How can protein-misfolding lead to dominant negative mutations and disease?
What is an example of a disease caused by this?

L8 S8

Answer 5

A mutant, misfolded protein can interfere with the function of the wild-type properly folded protein.

An example of this is keratin in epidermolysis bullosa and p53 in cancer. Both of these proteins form homopolymer and the pressence of a misfolded monomer weakens the function of the functional protein.

Question 6

How can protein-misfolding lead to gain-of-toxic function and disease?
What is an example of a disease caused by this?

L8 S7

Answer 6

Misfolded proteins can create a dominant phenotype with toxic functions.

An example of this is ApoE in some forms of Alzheimer’s which leads to mitochondrial dysfunction, neurite outgrowth inhibition, and protein accumulation

Question 7

How can protein-misfolding lead to amyloid accumulation and disease?
What is an example of a disease caused by this?

L8 S7

Answer 7

Amyloid fibers occur from proteins that are misfolded causing them to be insoluble and aggregate.

Diseases that occur in this manner include Alzheimer’s disease, Parkinson’s disease, and cataracts.