Lecture 7: Protein Folding Disorders

Question 1

Improper degradation

Answer 1

• Overactive cellular degradation systems (ERAD and autophagy) can contribute the accumulation of mutant, misfolded, incomplete degraded proteins
• Improper degradation of proteins can contribute to development of more severe diseases

Question 2

Improper localization

Answer 2

• For proper trafficking to target organelles, the protein must fold correctly
• Incorrectly folded proteins lead to improper subcellular localizations (Loss or gain of function-toxicity)

Question 3

Dominant-negative mutations

Answer 3

• A mutant protein antagonizes the function of the wild-type protein
• -> loss of protein activity, mutant protein presence interferes the function of WT protein at cellular and structural levels

Question 4

Gain-of-toxin function

Answer 4

-Protein conformational changes can cause dominant phenotypes
[Proteins become toxic]:
-APOE4 disrupts mitochondrial function; impairs neurite outgrowth
-(Cu/Zn) Superoxide dismutase (SOD1)
-Src kinases in cancer

Question 5

Amyloid Accumulation

Answer 5

• Amyloid fibers: insoluble protein aggregates
• These proteins: (Have VQIVY sequence** and can cause amyloid-related disease
• Lower order oligomers cause toxic effect (Amyloid dposits could be a protective mechanism)
• Sev amyloidogenic proteins form pore-like structure (disrupts the cell memb integrity)
• Misfolded forms of the protein are freq observed in (elderly- natural aging, individ’s with mutations in protein early in life)

Question 6

Cellular quality control system

Answer 6

Proteasomes, Autophagy, ERAD (ER-Associated Degradation)

Question 7

Diseases from improper degradation

Answer 7

CTFR in Cystic fibrosis and B-glucosidase in Gaucher’s disease
[mutant CTFR and B-gluc: both NO ERAD]

Question 8

Improper Localization disease

Answer 8

• AAT deficiency (alpha1-antitrypsin)
• Dual toxicity of AAT
• Liver and lung damage

Question 9

Dominant-negative mutations

Answer 9

• Mutations in keratin –> leads to weak cytoskeleton and can effect skin cells
• p53 (short half life of WT p53 bc of interactions with ubiquit MDM2)

Question 10

Gain of toxic function diseases

Answer 10

• ApoE in Alzheimer’s disease

- SRC kinases in cx

Question 11

Amyloid accumulation

Answer 11

Can result in neurodegen, cardiomyopathy, and catarcts*

Question 12

LO3: Know the protein aggregation mechanism in neurdegen disease

Answer 12

look up

Question 13

LO4: Know how proteins respond to stress via unfolded protein response (UPR)

Answer 13

Type of proteostasis; ER stress initiated signal pathway
-Unfolded or misfolded proteins accumulate in ER, causing ER stress

• ER stress initiates a signal pathway called UPR
• Pathway’s intention to save cell

Question 14

Keystones for environmental stressors (DRA)

Answer 14

To detect, respond, and to adopt

Question 15

UPRmt

Answer 15

Mitochondria proteasome