Lecture 7

Question 1

What are the 3 components of the CELLULAR quality control sys for maintaining protein homeostasis?

Answer 1

1. Proteosomes = digests ubiquitinated tagged proteins
2. Autophagy = cell eats cell; large garbage disposal
3. ERAD = ER Associated Degradation = can control quality; induces signal to translocate aberrant protein from ER to cytosol to be degraged by proteosome

Question 2

How does improper degradation contribute to protein-folding diseases?

Answer 2

Mutations can appear in a protein and make them semi-functional. The ERAD and autophagy sys over-reacts and eliminates the semi-functional protein which leads to a more severe disease

Question 3

How does improper localization contribute to protein-folding diseases?

Answer 3

A protein is synthesized in one tissue and once synthesized and properly folded, trafficked to its target tissue. If not folded properly, protein stays at the site of synthesis and leads to improper subcellular localization

Question 4

Improper subcellular localization leads to?

Answer 4

1. Loss of function ie AAT. Loss of AAT in the lungs bc misfolded stays in liver
2. Gain of Function-toxicity ie AAT stays in the ER of liver cells triggering apoptosis and incr inflammatory response

Question 5

How does Dominant-Negative mutations lead to protein folding diseases?

Answer 5

A mutant protein antagonizes the wild type protein. A mutant protein is weak and so interacting with WT proteins can cause survival of these weak proteins; a dominant-negative effects and loss of protein activity even if heterozygous. Now entire protein is compromised; hence dominant

Question 6

How does Gain of Toxic Function cause protein folding diseases?

Answer 6

A misfolded protein can cause dominant phenotypes by causing a protein to acquire a conformation that contributes to toxicity

Question 7

What are amyloid fibers?

Answer 7

Insoluble protein aggregates that form very strong, fibrous structure

Question 8

Why do proteins have the propensity to be amyloid fibers?

Answer 8

Have a common sequence: VQIVY

Question 9

Why can amyloidgenic proteins cause amyloid related diseases?

Answer 9

They all have presence of similar toxic protein conformations

Question 10

Amyloidgenic proteins disrupt cell membrane integrity how?

Answer 10

Form pore-like structures

Question 11

How do low order oligomers cause toxic effect?

Answer 11

Amyloid deposits could be a protective mechanism that cell uses to sequester the toxic species

Question 12

How do amyloid progress into amyloid plaques?

Answer 12

SEEDING NUCLEATION takes time. Amloidgenic intermediate aggregates and proliferate until SEED is formed. Builds SEED TOWER (fibril formation) and continues into plaque formation. Covalent modifications enhances amyloid fibrils ie hard to break and stays there (deposit)

Question 13

How do we remediate protein folding diseases?

Answer 13

Block the aggregate formation:

• small molecules as stabilizers
• site specific antibodies recognize sequence: VQIVY. (Doesn’t work as planned bc enzymes change shape)

Question 14

What are the keystones for environmental stressors?

Answer 14

DRA:
To detect
To respond
To adopt

Question 15

Intrinsic induction of stress defense programs and resulting adaptation can increase?

Answer 15

Life expectancy. Organism maintains its capacity to grown and reproduce

Question 16

How does caloric restriction prolong the life span (yeast-primates)?

Answer 16

Induce autophagy bc less reactive O2 production

Question 17

What is proteostasis?

Answer 17

Protein homeostasis. Mechanisms help lead proteins to proper function; tools cells are using:

• UPRs (ER and Mito)
• Cytosol HSR

Question 18

Cellular proteins fold via?

Answer 18

Chaperons

Question 19

Membrane and secreted proteins fold and mature in?

Answer 19

ER

Question 20

What is the last line of defense for proteostasis?

Answer 20

Apoptotic pathway

Question 21

What are the specific responses that help to cope with misfolded protein accumulation?

Answer 21

1. HSR = manages denatured proteins in the cytosol (HSF1)
   UPR^ER = ER stress (unfolded and misfolded accumulation) initiated signal pathway to save the cell
   UPR^MT = mito initiated signal pathway

Question 22

How are mitochondria chatty?

Answer 22

Talking for gene expression and sending different signals. Mitochondrial stress induces to tell the cell to transcribe mito specific genes

Question 23

How does a protein become toxic?

Answer 23

Transition form alpha helix to beta sheet which is characteristic of amyloid deposits

Question 24

The abnormal conformational transition from alpha helix to beta sheet exposes _

Answer 24

Hydrophobic aa residues and promotes protein aggregation

Question 25

Why does H20 differ in solid and liquid for eg snow vs rain accumulation and properties?

Answer 25

Snow accumulates more than water does because snow is the solid form of water which means that it has longer and more optimal H bonds than liquid rain. Snow’s low density is associated with longer H bonds. Density is the measure of how tightly packed atoms/molecules are, so the less dense something is the less tightly packed molecules will be thus explains why we get more snow than rain for the same amt of water. At temps below freezing water molecules have less energy and motion when compared to liquid water at temps above freezing. Temps below/at freezing promote a more stable H bond. If temps begin to incr, water molecules of snow will have more motion and energy which will create an environment for suboptimal H bonds. This temp increase also incr the density of water, so accumulation of snow will decrease effecting the depth of snow one will get for the same amount of water