Class 11: Protein Folding-agbas Flashcards
Molecular chaperons
Cellular quality control system: Proteosomes, autophagy, ERAD (ER-asso. Degradation)
Maintenance of protein homeostasis=critical
5 main mechanisms of toxicity in cell:
Improper degradation
Improper localization
Dominant negative mutations
Gain-of-toxic function
Amyloid accumulation
First known protein-misfolding Dz
Sickle cell anemia
Single point mutation changes E (glu) to V (Val) in the beta-globulin chain of Hb
Exposing a hydrophobic patch that leads to polymerization
Reduces elasticity of RBC
Causes extreme pain, extensive tissue destruction, and anemia
Sickle cell anemia
Overactive cellular degradation systems (ERAD and autophagy) can contribute the accumulation of mutant, misfolded, incomplete degraded proteins
This can contribute to the development of more severe Dz
Improper degradation
ERAD
Endoplasmic reticulum asso. Degradation
For proper trafficking to target organelles, the proteins must fold correctly
Incorrectly folded proteins lead to improper subcellular end point
Leads to:
Loss of function and gain of function-toxicity.
Improper localization
A mutant protein antagonizes the function of the WT protein
- loss of protein activity
- mutant protein presence interferes the function of the WT protein at cellular and structural levels
Dominant negative mutations
5 mechanisms of protein misfoldings leading to toxicity
Improper degradation Improper localization Dominant negative mutations Gain of toxic function Amyloid accumulation
Protein conformational changes can cause dominant phenotypes
- Proteins become toxic
- -APOE4 disrupts mito. Function; impairs neurite outgrowth.
- -Cu/Zn-superoxide dismutase (SOD1)
- -Src kinases in CA
Gain of toxic function
- Insoluble protein aggregates
- have VQIVY sequence
- lower order oligomers cause toxic effect; deposition could be a protective mechanism
- several amyloidogenic proteins form pore-like structure which disrupts the cell membrane integrity.
- misfolded forms of the protein are frequently observed in: the elderly(natural aging) and individuals w/ mutations in the protein early in life
Amyloid accumulation
how amyloid progress to amyloid plaques?
- seeding (nucleation)
- Fibrin formation
- Deposit
Why is knowledge about protein folding significant?
Opens new avenues for Rx discovery
Common amyloidogenic preotein
Primary carrier of hormone thyroxine and a retinol transporter
TTR
Transthyretin (protein)-4 identical polypeptides
How can Rx potentially remediate blocking the aggregate formation?
- Small molecules can act as stabilizer
- site-specific antibodies
- recognize conformational changes
- can be sequence specific(VQIVY)
Organism maintains its capacity to grow and reproduce
Ketones for environmental stressors (DRA)
Intrinsic induction of stress defense programs and resulting adaptation can increase life expectancy
Rxn to stress and adaptive response
Keystones for environmental stressors:
DRA
To Detect
To Resp
To adopt
How can hermetic stress affect protein folding?
Applying moderate levels of stress could trigger beneficial and adaptive stress defense pathways, allowing longer life
Caloric restriction prolongs the lifespan
Maintenance of protein homeostasis
Cellular and organismal functionality req’s: protein production,folding, and degradation
Unfolded protein responses (UPR)
Complex pathways to ensure protein homeostasis in different compartments
- CYTOSOL
- ER(UPR)
- MITO. (UPR)
- -more recently discovered;complex relationship btw nucleus and mito.
Proteostasis
Methods of proteostasis:
- Cellular proteins folded by chaperons
- membrane and secreted proteins fold and mature in ER
- specific response help to cope w/ misfolded proteins accumulation
- apoptotic pathway is the last line of defense
- Heat shock response (HSR)
- UPR-ER is mediated; inositol req’ing element 1 (IRE1),PERK, ATF6
Manages denatured proteins into the cytosol (HSF1)
Heat shock response (HSR)
Composed of ~1500 proteins.
Encoded by both nuclear and mito. Genome.
13 essential proteins of ETC are encoded by mtDNA.
2 major mito. Chaperon systems 70 and 60-10.
Protein quality control (PQC) proteases; specific each mito. Compartment. Recognize and degrade the proteins dont fold and properly assembled.
UPR-mito. Senses the overload of the QC system capacity
-activates the transcription of nuclear encoded protective genes; re-establish the mito. Homeostasis
- The signal transmission from the unfolded/misfolded mito. Proteins to the nucleus cannot be accomplished using HSR and UPR-er system.
- the best described system is the retrograde response (RTG)-metabolic adaptations in response to decreased mito. Activity in yeast.
- RTG doesnt modulate the mito-chaperons expression;UPR-mt has a distinct regulatory mechanism
- stochiometric imbalance among the ETC protein complexes (comp 1,3,4,5) activates UPR-mt system
UPR-mt signaling
