Biochem Lecture #6 (mestril) Flashcards
In an unfolded state proteins are ______.
As they keep folding they are trying to achieve____.
In an unfolded state, proteins are at their highest Gibbs free energy.
As they keep folding, they are trying to achieve lowest delta G.
Note: amyloid fibers are at the lowest possible delta G (this is why its impossible for chaperone proteins to unfold and bring them back)
What are the functions of chaperone proteins?
Chaperone proteins:
- prevent aggregation
- reverse aggregation
- regulate signal transduction
- mediate cell to cell signaling
Name the location and function of the following heat shock proteins:
HSP90, HSC70, HSP70, HSP60, HSP10, Ubiquitin
HSP90: cytosol/nucleus, forms chaperone complex
HSC70: cytosol, consituitive chaperon
HSP70: cytosol/nucleus, inducible molecular chap
HSP60: mitochondria, chaperonin complex member
HSP10: mitochondria, chaperonin complex member
Ubituitin: cytosol/nucleus, protein degradation
The chaperones play a crucial role in protein folding starting from _______________.
Chaperones stabilize ______________.
The main chaperones involved in stabilization and folding of nascent polypeptides is_____ and ____.
Chaperones play a crucial role in protein folding starting from the ribosome to the final native protein.
Chaperones stabilize nascent polypeptides on ribosomes and quickly initiate folding.
Main chaperones involved: Hsp70 and Hsp 40.
Those chaperones also transport final completed polypeptide to other chaperone complexes where protein folding can be continued:
chaperonin complex made up of hsp 60 and hsp10
Explain the pathway of Hsp’s that interact with peptides right after they leave the ribosome.
What are the three major outcomes for a newly synthesized protein?
So, the first chaperone to bind is Hsp40, and then Hsp 70 binds and assists in the proper folding. Then, the cell can aggregate,
get handed off to degradation pathway (ubiquitin)
or get handed to Hsp90 which folds even more
Explain how Hsp90 works.
Hsp 90 is a dimer. It is opened like a v. It closes using ATP, and helps with even bigger protein folding.
Explain how the heat shock response thermometer works.
What is the thermometer?
The “heat shock thermometer” is Hsp90.
The way the system works is that under stress, the ATP binding pocket on HSP90 is blocked, which causes HSF1 to fall off, get phosphorylated, trimerize and then activate genes on the DNA to produce more heat shock proteins.
What are the two chaperonin systems in eukaryotes?
How do they work?
Eukaryotes: hsp60-hsp 10 in the mitochondria
TRiC (cytosol)
are both chaperonin systems
THey are long cylindrical multisubunit structures that bind unfolded polypeptides in their molten-globule state within their central hydrophobic cavity. There are 14 of them, 7 units in wht barel.
In eukaryotes, proteomes are highly complex.
800 factors
These components make up the proteostasis network….. (what does that network do?)
Proteostasis network integrates general and specialized chaperone components for proper protein folding and trafficking with the machinery for disaggregation and proteolytic degradation of irreversibly misfolded proteins.
What happens to this proteostasis network when it collapses?
The whole network works great, but as you age you decrease the expression of chaperones, which declines the degradaton system so a lot more unfolded proteins escape. (The collapse occurs for many reasons, one is aging).
What disease is a result of protein misfolding?
Which diseases are a result of protein aggregation?
Cystic Fibrosis: misfolded protein
Alzhiemer’s, Huntington’s, Parkinson’s, Prion Diseases are all due to aggregated proteins
Explain Cystic Fibrosis.
Defective protein is CFTR (which is a chloride pump)
When the protein is misfolded, it does not work
Chloride then accumlates inside of the cell
High intracellular chloride concentration makes cells take up of water from surrounding mucus from osmosis, resulting in thickening of the mucus.
Homozygous recessive disease
Explain Prion Diseases/BSE/CJD
Prion diseases, the culprit is PrP normally present in the brain. The abnormal version of this protein is infectious and the prion PrPsc forms various sized protein aggregates, which are resistant to treatment.
The abnormal PrPsc have lots of beta sheets (the normal version has alpha helixes), and converts normal proteins into Prpsc.
Explain Alzheimer’s Disease
Alzheimer Disease is due to intracellular aggregates of the tau protein. These plaques contain beta amyloid peptides attached to the cell membrane of neurons.
Explain Huntington’s Disease
Huntington’s Disease is caused by a mutation that’s an expansion of repeated sequence CAGCAGCAG within the gene for the protein huntington, encoding polyGln sequences in the protein.
Protein aggregates accumulate in nuclei and cytoplasm of neurons in the striatum region of the brain.
