Lecture 8: Protein folding disorders

Question 1

Improper degradation

Answer 1

Overactive cellular degradation systems (ERAD) can contribute to accumulation of mutant, misfolded, incomplete degraded proteins

Question 2

Improper localization

Answer 2

Misfolded proteins lead to improper subcellular localization causing:

• loss of function
• gain of function toxicity

Question 3

Mutant protein effect on WT protein

Answer 3

Mutant protein antagonizes the function of WT protein

• loss of protein activity
• interferes with function of WT protein at cellular and structural levels

Question 4

Gain of toxic function

Answer 4

Protein conformational changes can cause dominant phenotypes
-APOE4 disrupts mitochondrial function, impairs neurite outgrowth
Src kinases in cancer

Question 5

Amyloid fibers are what, and contain what sequence

Answer 5

Insoluble protein aggregates

VQIVY

Question 6

How can amyloidogenic protein aggregates effect cells?

Answer 6

They can form pore-like structures, disrupting the membrane integrity

Question 7

What enhances the formation of amyloid fibers

Answer 7

Covalent modifications

Question 8

Potential remediation processes

Answer 8

Blocking the aggregate formation by:

• small molecules (chaperones) as stabilizer
• Site specific antibodies recognize conformational changes or specific sequences such as (VQIVY)

Question 9

What are the keystones for environmental stressors

Answer 9

Detect
Adapt
Respond

Question 10

What can increase life expectancy

Answer 10

Intrinsic induction of stress defense programs resulting in adaptation

Question 11

Hormetic stress

Answer 11

Applying moderate levels of stress could trigger beneficial adaptive stress pathways, allowing longer life

Question 12

Cellular and organismal functionality requires

Answer 12

Protein production
Folding
Degredation

Question 13

Proteostasis pathway in Cytosol

Answer 13

HSR

Question 14

Proteostasis pathway in ER

Answer 14

UPR(ER)

Question 15

Proteostasis pathway in mitochondria

Answer 15

UPR(mt)

Question 16

Membrane and secreted proteins fold and mature where

Answer 16

ER

Question 17

What is the last line of defense for misfolded proteins

Answer 17

Apoptotic pathways

Question 18

HSR

Answer 18

Heat shock response

Manages denatured proteins in the cytosol (HSF1)

Question 19

Response to unfolded/misfolded proteins in ER

Answer 19

UPR-ER
Increases protein chaperones
Increase rate of ERAD
Decrease protein production
-Apoptosis is last resort

Question 20

PQC proteases

Answer 20

Part of UPR in mitochondria
Specific to each mitochondrial compartment
Recognize and degrade misfolded proteins

Question 21

Overload of quality control system

Answer 21

UPR mito can sense overload of QC system
-Activates transcription of nuclear encoded protective genes
Re-establish mitochondrial homeostasis