Protein folding, Heat shock proteins and disease involved with protein misfolding
Heat shock proteins
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Transcript of Heat shock proteins
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HEAT SHOCK PROTIENS
- Purvi Shah
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Proteins are the major components of living
organisms and perform a wide range of essential
functions in cells
Proteins regulate metabolic activity, catalyze
biochemical reactions and maintain structural integrity
of cells and organisms
Proteins
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Structural Levels of ProteinsPrimary Secondary
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Protein Denaturation
The activity of a protein depends on its three-dimensional structure.
Intramolecular bonds, especially hydrogen bonds, maintain the structure.
Hydrogen bonds may break when the pH drops or the temperature rises above normal denaturing the protein
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Protein Denaturation with extreme pH or Temp.
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Tempenviron
Tempcell
Folded Proteins
Unfolded Proteins Aggregates
Loss of ProteinFunction
Networkfailure
Death
Cell
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Interesting storyF. Ritossa –1960 discovered the heat shock (HS) response while observing the salivary cells of Drosophila and named them HSP’s
My name is Chaperone
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How do Chaperones work? One major function of chaperones is to prevent both newly synthesised
polypeptide chains and assembled subunits from aggregating into nonfunctional structures
High temperatures and other stresses, such as altered pH and oxygen deprivation, make it more difficult for proteins to form their proper structures and cause some already structured proteins to unfold
Heat Shock Proteins are induced rapidly at high levels to deal with this problem
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Different Types of Heat Shock Proteins
Heat Shock Proteins are classified by their
molecular weight, size, structure, and function.
They are divided into several families, namely -
1. HSP100
2. HSP90
3. HSP70
4. HSP60 (chaperonin)
5. Small Heat Shock Proteins/ (alpha)-
crystalline proteins
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HSP100
Functions -solubilizes protein aggregates thereby dissociating them -facilitates proteolysis -essential in yeast for acquired thermotolerance -essential for yeast prion propagation
6-7 monomer ATP no co-chaperon is required
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HSP 90
stabilizes proteins prior to complete folding or activation
forms stable complexes with inactive glucocorticoid receptor and other
transcription factors
most abundant non-ribosomal protein (cytosolic version)
most abundant protein in endoplasmic reticulum (ER version)
dimer
ATP
HoP and p23
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HSP90 interacts with HSP40, HSC70/HSP90 organizing protein(HOP), and co-chaperones to bind and stabilize newly synthesized substrate/client proteins. This ATPregulatedcycle of substrate binding is critical to the activation of many oncogenic signaling molecules.
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HSP70
monomer
ATP
DnaJ and GrpE
assists in protein transport into mitochondria and the endoplasmic
reticulum
protects proteins under stress
stabilizes proteins prior to complete folding
transports across membranes and proteolysis
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HSP70 works with HSP40 to capture and transfer misfolded client proteins to prefoldin and other chaperonins for refolding
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HSP60 14-16 monomer ATP GroES and GroEL mediate the native folding of proteins through cooperation of HSP70 and 60
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A) Reconstruction of the GroEL
structure with and without the
GroES
™lid∫ from cryoelectron microscopy
pictures.
B) Model of the GroEL chaperone
cycle. Two misfolded proteins
(green
and blue) are simultaneously folded
in a phase-shifted manner. The red
circles
symbolize the hydrophobic
substrate binding sites of GroEL
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sHsp
8-24 monomer
exhibit chaperone activity in vitro and thermoprotection in vivo
produced at significant levels in cells experiencing heat stress
most are heat inducible, but some are synthesized in unstressed
conditions-such as for cell development
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Denatured or unfolded substrates bind to the hydrophilic surface of small HSP complexes and prevent the substrate from aggregating.The substrate either stays sequestered or is released to be refolded or degraded.
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Why Don't Heat Shock Proteins Denature?
Better Hydrogen Bonds
Better Hydrophobic Internal Packing
Enhanced Secondary Structure
Helix Dipole Stabilization
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Protein denaturation by temperature
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