Lecture 7 Flashcards
What are the 3 components of the CELLULAR quality control sys for maintaining protein homeostasis?
- Proteosomes = digests ubiquitinated tagged proteins
- Autophagy = cell eats cell; large garbage disposal
- ERAD = ER Associated Degradation = can control quality; induces signal to translocate aberrant protein from ER to cytosol to be degraged by proteosome
How does improper degradation contribute to protein-folding diseases?
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
How does improper localization contribute to protein-folding diseases?
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
Improper subcellular localization leads to?
- Loss of function ie AAT. Loss of AAT in the lungs bc misfolded stays in liver
- Gain of Function-toxicity ie AAT stays in the ER of liver cells triggering apoptosis and incr inflammatory response
How does Dominant-Negative mutations lead to protein folding diseases?
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
How does Gain of Toxic Function cause protein folding diseases?
A misfolded protein can cause dominant phenotypes by causing a protein to acquire a conformation that contributes to toxicity
What are amyloid fibers?
Insoluble protein aggregates that form very strong, fibrous structure
Why do proteins have the propensity to be amyloid fibers?
Have a common sequence: VQIVY
Why can amyloidgenic proteins cause amyloid related diseases?
They all have presence of similar toxic protein conformations
Amyloidgenic proteins disrupt cell membrane integrity how?
Form pore-like structures
How do low order oligomers cause toxic effect?
Amyloid deposits could be a protective mechanism that cell uses to sequester the toxic species
How do amyloid progress into amyloid plaques?
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)
How do we remediate protein folding diseases?
Block the aggregate formation:
- small molecules as stabilizers
- site specific antibodies recognize sequence: VQIVY. (Doesn’t work as planned bc enzymes change shape)
What are the keystones for environmental stressors?
DRA:
To detect
To respond
To adopt
Intrinsic induction of stress defense programs and resulting adaptation can increase?
Life expectancy. Organism maintains its capacity to grown and reproduce
How does caloric restriction prolong the life span (yeast-primates)?
Induce autophagy bc less reactive O2 production
What is proteostasis?
Protein homeostasis. Mechanisms help lead proteins to proper function; tools cells are using:
- UPRs (ER and Mito)
- Cytosol HSR
Cellular proteins fold via?
Chaperons
Membrane and secreted proteins fold and mature in?
ER
What is the last line of defense for proteostasis?
Apoptotic pathway
What are the specific responses that help to cope with misfolded protein accumulation?
- 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
How are mitochondria chatty?
Talking for gene expression and sending different signals. Mitochondrial stress induces to tell the cell to transcribe mito specific genes
How does a protein become toxic?
Transition form alpha helix to beta sheet which is characteristic of amyloid deposits
The abnormal conformational transition from alpha helix to beta sheet exposes _
Hydrophobic aa residues and promotes protein aggregation
Why does H20 differ in solid and liquid for eg snow vs rain accumulation and properties?
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
