Protien Folding Disorders Flashcards
What is the first known protein folding disease?
Sickle cell anemia
SIckle cell anemia is caused but what type of problem? What effect does it have on the original protein (heme)?
Sickle cell anemia is caused by a point mutation E -> V
Causes a hydrophobic patch to be exposed and polymerication
Elasticity of RBC is reduced: pain, tissue damage and anemia
What is improper degration and the examples of it?
Overactive cellular degration systems (ERAD -Endoplasmic Reticulum Associated Degration) leads to accumulation of mutant, misfolded, incompletely degraded proteins.
CFTR mutation and Cystic Fibrosiss
B-glucosidase mutation and Gaucher’s disease
Cystic fibrosis
Mutation in the membrane channel CFTR (delta-F508) that causes a misfolding with partial function but gets tagged with HSP90 and AHA1 and degraded by ERAD
Gaucher’s Disease
Improper degration mutation that causes misfolding and the b-glucosidase, that’s partially functional, never makes it to the lysosome
Missing chaperone.
Improper localization and the examples?
Misfolded proteins get mistrafficated and end up in the wrong place where they have a loss-of-function and a gain-of-function toxicity.
Alpha1-antitrypsin
Dominant Negative Mutations
A mutant protein that antagonizes the function of the wild-type protein
The mutant interferes with WT proteins at cellular and structural levels
Keratin- mutations lead to weaker intermediate filaments. Dom-Neg: WT works with mutant
P53 - transcription factor - accumulation of tetramers with mutant- stabalized by hsp90
Amyloid accumulation
Aggregation of amyloid fibers - insoluble protein.
Sequence VQIVY
Formations of oligomers
-toxic
Amyloid deposits - protective mechanisms
Amyloid proteins can cause pore like structures
What’s the stages of amyloid progressing to amyloid plaques?
Seeding - nuceleation
Fibril formaitaon
Deposit
what’s an organisms response to environmental stressors? On a celular level
DRA
DETECT
RESPOND
ADOPT
Adaption can increase life expectancy
Plaque formation is an example of adopting
What is hormetic stress?
Moderate levels of Stress that is beneficial because it triggers adaptive stress defense pathways
Gets the response going faster
-> allows longer life
Ex. Caloric restriction
What are HSR, UPRer and UPRmt important for?
They help maintain protein homeostasis
HSR: manages denatured proteins in cytosol and misfolded protein accumulation
UPRer: in the ER - helps with misfolded protein accumulation
UPRmt: mitochondrial, picks up the slack when PQC is over loaded
What’s the function and relationship of PQC- protein quality control protease and UPRmt?
PQC proteases recognize and degrade misfolded proteins
UPRmt senses when QC is at max capacity
-activates the transcription of nuclear encoded protective genes.
Imbalance in ETC complexes also activates UPRmt
