Protein Folding Disorders Flashcards
What are the key modulators in maitenance of protein homeostasis
Molecular chaperons
Cellular quality control systems
- Proteasomes
- Autophagy
- ERAD (ER-Associated Degradation)
what are the 5 ways protein folding can lead to disease
- Improper degradation
- Improper localization
- Dominant negative mutations
- Gain-of-Toxic function
- Amyloid Accumulation
What is the first known protein misfolding disease
Sickle cell Anemia
- results from a single point mutation changes an (Glu) to (Val) in the beta-globulin of hemoglobin
overactive cellular degradation systems (____ and _____) can contribute to the degradation of mutant, misfiled, incomplete proteins
ERAD and Autophagy
ERAD stands for
Endoplasmic Reticulum Associated Degradation
What is mutant CFTR involved in treated
CFTR is a membrane ion channel which mutants in lead to cystic fibrosis due to the improper degradation of the somewhat functioning protein. It can be treated by inhibiting the HSP90 and AHA1 chaperones that degrade the partially functioning enzyme thus allowing for some function at membrane and not ERAD
What is Gaucher’s disease and how is it treated
Gaucher’s disease is a mutation in Beta-glucosidase, which is lysosomal enzyme. The improper degradation of this enzyme leads the disease. Thus it is currently treated with enzyme replacement but they are working on pharmacological chaperones that would bind and stabilize B-Glucosidease to avoid ERAD and allow it to travel to lysosome
Improper localization leads to
loss of function
gain of function/toxicity
for proper trafficking to target organelles, the proteins must fold
correctly
What is an example of improper localization and how is it treated
- AAT deficiency
- mutation in AAT halt systemic secretion of the protein in the liver
- Thus the lungs, the ultimate destination are low on AAT and the liver is overloaded
- This leads to emphysema in the lungs and liver disease
- Treatment
- Treated with the replacement of AAT in the lungs and autophagy in the liver to clear the aggregations and prevent liver damage
What is are two examples of dominant-negative protein mutations
Keratin in epidermolysis bullosa simplex
p53 in Cancer
explain who the keratin in epidermolysis bullosa simplex has a double-negative effect
The Mutant keratin is able to associate with the WT(wild type) protein and form weak intermediate filaments
What are the therapueutic options for Epidermolysis bullosa simplex
identifying chemical chaperones that will prevent aggregation of mutant keratin
Explain how mutations in p53 in cancer are dominant-negative protein mutations
p53 is a transcription factor that regulates multiple pathways to protect cells form stresses such as DNA damage. WT p53 has a short half life due to its interactions with ubiquitin ligase MDM2. Mutant p53 is unable to bind MDM2 and is specifically stabilized by binding chaperones, including Hsp90. Thus, tetramers with mutant p53 accumulate, but are not able to activate protective gene pathways
what are some roles of WT p53
Cell cycle metabolism Senescence Apoptosis DNA damage Aging
How is Dominant -negative mutation to p53 treated
With Nutlins, a family of compounds that inhibit MDM2 and stabilize WT p53
Dominant negative mutations
A mutant protein antagonizes the function of the wild-type protein
- Loss of protein activity
- Mutant protein presence interferes with the function of the WT protein at cellular and structural levels
Two examples of Gain of toxic function
- ApoE in Alzheimer’s disease
- SRC kinase in cancer
explain ApoE mutation in Alzheimer’s disease
ApoE3 (WT) is replaced with ApoE4, which leads to a change in protein structure so that a salt bridge is between amino acids R61 and E255. this prevents the helix form extending
How is ApoE mutation treated
small molecules have been discovered that block the improper conformation and prevent defects associated with ApoE4 expression.
Explain SRC kinases in cancer
mutant form of SRC, v-SRC, is constitutively active and oncongenic due to loss of the autoinhibitory region containing Y527, which is regulated by phosphorylation in the WT protein. v-SRC is dependent on chaperons, including HSP90 , for folding and activation. in the absence of HSP 90, the protein is targeted for degradation
treatment for v-SRC in cancer
HSP90 inhibitors
Amyloid accumulation can occur in
neurogenerative diseases, cardiomyopathies, and cataracts
What are the aggregated proteins in alzheimer’s disease
AlphaBeta
Tau
