Lecture 8 Flashcards
What do proteasomes, Autophagy, and ERAD (ER-associated Degradation) all have in common?
they are all methods/tools of the cellular quality control system
State the 5 problems that can arise due to improper protein folding
- Improper degradation
- Improper localization
- Dominant negative mutations
- Gain-of-toxic function
- Amyloid accumulation
generally explain 2 methods that can lead to “Improper degradation” caused by protein misfolding
Overactive ERAD and autophagy can lead to improper degradation due to misfolded proteins
generally explain 2 examples of “improper localization”
caused by protein misfolding
Loss-of-function and Gain-of-function toxicity caused by misfolding are both examples of improper localization
generally explain 2 examples of “Dominant negative mutations” caused by protein misfolding
A mutant protein antagonizes the function of the wild-type protein and causes one of the following:
Loss of protein activity
mutant protein presence interferes with the function of the WT protein at cellular and structural levels
generally explain 3 examples of “Gain-of-toxic function” caused by protein misfolding
protein misfoldings can cause dominant phenotypes that cause the following:
APOE4 disrupts mito function, which impairs neurite outgrowth
(Cu-Zn) Superoxide dismutase (SOD1)
Src kinases in cancer
Give 2 characteristics of Amyloidogenic proteins (sequence and function).
Characteristics:
Have a VQIVY sequence
Can cause amyloid-related diseases
Define Amyloid fibers.
Amyloid fibers: insoluble protein aggregates
Explain how an amyloid deposit could be a protective mechanism
an amyloid deposit may be created in an attempt to “isolate” a defective/misfolded protein to battle it’s negative functions
what order of oligomers can cause a toxic effect? given an example of a toxic effect that an amyloidogenic protein can conduct on the cell membrane.
low order oligomers can cause a toxic effect.
Several amyloidogenic proteins form a “pore-like” structure that disrupts the integrity of the cell membrane
state the 2 demographics that misfolded proteins are most commonly observed in.
elderly people (due to the aging process)
individuals with mutation in their proteins that occurred early in life
True or False:
Amyloid fibrils cannot be “rescued” once they have been formed. explain.
true
their conformation is so low in energy that we have not yet found a treatment that can unfold the proteins from this conformationally stable state. (you can’t surgically remove it either bc its too invasive on the brain)
Describe the stepwise process by which amyloid plaques are formed.(3 steps)
- seeding occurs (nucleation)
- Fibril formation occurs
- amyloid fibers are deposited
what enhances the formation of amyloid fibers?
covalent modifications enhance the formation of amyloid fibers
Explain how small molecules and site-specific antibodies can block the formation of misfolded protein aggreagates
small molecules can act as a stabilizer
Site-specific antibodies can recognize conformational changes that occur AND sequence specific issues (like VQIVY)
Intrinsic induction of stress defense programs can result in _____ and can increase ____ ____.
adaptation
life expectancy
State the 3 keystones for environmental stressors
to detect
to respond
to adopt
(DRA mnemonic)
Give an example of hormetic stress and then give an example of it that can lead to a longer lifespan
Hormetic Stress: moderate level of stress that can trigger beneficial/adaptive stress defense pathways, which may lead to loner life (what doesn’t kill you makes you stronger)
caloric restriction
Define proteostasis. Then state the 3 activities (of both cellular and organismal functionality) it requires
Proteostasis: the maintenance of protein homeostasis, which is usually carried out via UPR’s (unfolded protein responses)
Requires:
Protein production
Folding
Degradation
Describe the origin/setting of the following pathways that function to maintain proteostasis:
HSR:
UPR^ER:
UPR^mt:
HSR: (heat shock response) manages denatured proteins in the cytosol using HSF1
UPR^ER: ER stress initiated signal pathway
UPR^mt: Mitochondria initiated signal pathway
Cellular proteins are folded by what?
chaperons
Explain the synthesis/maturation of membrane and secreted protiens
membrane and secreted proteins fold and mature in the ER
What is the last line of defense when it comes to managing misfolded proteins?
apoptosis (via an apoptotic pathway)
State the 3 effects that occur when the UPR (unfolded protein response) signal pathway is activated
(UPR^ER and UPR^mt are examples of UPR)
- Increase in protein chaperones
- Increased rate of ERAD
- Decreased protein production
What are the 2 main players in the mitochondrial chaperon system?
mtHSP70
Multimeric HSP60-HSP10 machinery in the matrix (of the mito)
Describe PQC proteases
PQC (protein quality control) proteases recognize and degrade the proteins that don’t fold or are improperly assembled
True or False:
There are specific PQC proteases for each mitochondrial compartment. explain.
True
Explain how UPR^mt is initiated and what it does after it is initiated
UPR^mt senses the overload of the QC system capacity and activates the transcription of nuclear encoded protective genes in order to re-establish mitochondrial homeostasis
