Lecture 39: Protein Folding Disorders

Question 1

Improper degradation

Answer 1

Overactive ERAD degrades mutated proteins that may be partially functional
Ex: CFTR chloride channel protein in cystic fibrosis
Therapy: Target chaperone system to save partially functional protein

Question 2

Improper localization

Answer 2

Mutated protein accumulates at the site of synthesis instead of being sent to destination; toxic at site of synthesis and destination site lacks needed protein
Ex: AAT deficiency in the lung; accumulates in the liver
Therapy: enzyme replacement in lung

Question 3

Dominant negative mutations

Answer 3

Mutant protein is not functional, but interferes with wild-type protein
Ex: Skin disease where wild-type keratin and mutant keratin form weak intermediate filament due to mutation
Therapy: Identify chaperones

Question 4

Gain-of-toxic Function

Answer 4

Conformational changes in mutant protein causes it to become toxic
Ex: APOE becomes APOE4, forming a salt bridge that functions as toxic material in Alzheimers dx
Therapy: Block molecules with improper conformation

Question 5

Amyloid Accumulation

Answer 5

Amyloidogenic proteins have VQIVY sequence which eventually form amyloid fibers, plaques
Ex: usually age related
Therapy: antibodies that disrupt aggregate formation of fibers

Question 6

What are the keystones for environmental stressors?

Answer 6

detect, respond, adopt

Question 7

Hormetic stress

Answer 7

Moderate levels o stress can trigger beneficial/adaptive defense mechanisms; such as caloric restriction

Question 8

Proteostasis

Answer 8

Maintenance of protein homeostasis through unfolded protein responses (cytosol-HSP, ER-UPRer, Mito-UPRmt)

Question 9

What is the last line of defense if chaperones and UPRs are not able to properly fold proteins?

Answer 9

Apoptosis