Heat Shock Proteins Flashcards
BRAIN AMYLOIDOSES
Protein aggregates with typical amyloid structure are common among many different neurodegenerative disorders, collectively defined BRAIN AMYLOIDOSES (AD, PD, ALS, HD, polyQ diseases, etc)
Amyloid structure & toxicity
A common feature of all forms of amyloid aggregates is the initial acquisition of a b-sheet secondary structure that may be responsible for shared mechanisms of toxicity
Structure of amyloid aggregates over time
Natively unfolded can go into protofibril –> fibril or toxic pore
Or natively unfolded proteins can form alternative conformations (with increased/decreased toxicity depending on additional factors)
Fibrillary structures
Fibrillary structures often display the properties of amyloid (~10 nm-wide fibrils
with crossed B-pleated sheet structures)
Toxic pore structure
pores insert into membrane –> leakage of material causing toxicity
Ideal protein folding and what dictates it
Primary structure (aa’s) dictate protein folding and favours the most energetically/thermodynamically stable conformation
BUT cellular enviro/crowding can alter this folding
How the cellular enviro can alter folding
- the cytosol is packed with proteins and this enviro can lead partially folding proteins to misfold leading to misfolding and aggregation
- but chaperones can help direct proteins into certain conformations
T/F only partially folded/unfolded proteins risk misfolding
FALSE
even proteins that are already folded risk unfolding–esp when under cellular stress
Chaperone–roles
- can help with refolding or may push proteins to wither a disordered aggreagtes or amyloid fibrils
- can also help deliver misfolded proteins for degradation (proteasomal or autophagy)
Chaperone–role brief
refolding AND removal of misfolded proteins (proteostasis)
Molecular chaperones
enhance the efficiency of de novo protein
folding and promote the refolding of misfolded proteins
Chaperones in healthy cells
In healthy cells, misfolded proteins are refolded correctly through the intervention of molecular chaperones or are degraded by the proteosomal system or by autophagy
Chaperones as we age
With aging, the induction and/or activity of molecular chaperones and the function of the proteosomal system decrease, favoring accumulation of toxic misfolded proteins (impaired proteostasis).
This may account for the late onset of neurodegenerative diseases that are linked to protein aggregation.
Molecular chaperones have roles in
- proteosomal degradation
- macroautophagy
- non-conventional secretion
= removal of misfolded proteins to decrease toxic burden
And folding and refolding
Monomers misfolding
While acquiring a misfolded conformation is often thermodynamically favourable the conversion back may require more energy to occur
- molecular chaperones can intervene and help return the protein to its native conformation
Molecular chaperones and direction of monomer folding
by stabilizing a native or misfolded monomeric conformation chaperones, incl. HSP 40/70, might prevent the intramolecular transition that gives rise to spherical and annular oligomers WHILE simultaneously stabilizing those that lead to inclusion body formation (amorphous aggregates and fibrils) –> likely less toxic
heat shock protein HSP) families
Five main families of ATP-binding, heat shock proteins (HSP):
HSP100, HSP90, HSP70, HSP40 and small HSPs (sHSPs)
HSP90
Cytosolic dimeric chaperone that stabilizes misfolded proteins and regulates the activity of various signalling proteins:
- steroid hormone receptors
- tyrosine kinases
- nitric oxide synthase
- calcineurin, etc.
HSP70
assists in the stabilization and folding of many substrates and is found in most cellular compartments.
HSP40
co-chaperones that bind misfolded proteins and target them to HSP70.
In complex with HSP70, HSP40 proteins stimulate ATP hydrolysis, resulting in a conformational switch that facilitates the folding of non-native protein substrates.
