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Printable Handouts
Navigable Slide Index
- Introduction
- What is a molecular chaperone?
- Free energy landscape
- The role of chaperones
- How did it all start?
- “Unfolding enzymes”
- The discovery of Hsp60 (GroEL) and Hsp70 (DnaK)
- The RubisCO binding protein
- Overexpression of RubisCOL and RubisCOS
- RubisCO assembly experiment
- In vitro experiments
- Chaperones can ‘proof-read’ the quality of protein folding
- Evolutionary-inferred functional hierarchy of the chaperone network (I)
- Evolutionary-inferred functional hierarchy of the chaperone network (II)
- Evolutionary-inferred functional hierarchy of the chaperone network (III)
- The structures of Hsp70 (and of DnaJ or Hsp40)
- Hsp70s are abundant
- Physiological and stress-related functions of Hsp70s
- Cochaperones enable the protein to have many different functions
- Hsp70 actively unfolds misfolded structures in aggregates
- The disaggregation activity of Hsp70
- The kinetic parameters and energy cost of Hsp70
- ATP-fuelled Hsp70/DnaJ/NEF unfold inactive luciferase monomers
- Unfolding consumes ATP
- Unfolding consumes ATP, native refolding is spontaneous
- The chaperone cycle of Hsp70 as an ATP-fuelled polypeptide unfoldase
- 5 ATPs are required
- What is the nature of the Hsp70 substrate: is it unfolded or misfolded?
- Isolation of natively-unfolded and a stable oligomeric form of α-synuclein
- Oligomeric α-synuclein inhibits Hsp70-mediated refolding
- The fluorescence of the unique tryptophan in Hsp70 (DnaK) (I)
- The fluorescence of the unique tryptophan in Hsp70 (DnaK) (II)
- The fluorescence of the unique tryptophan in Hsp70 (DnaK) (III)
- Model for substrate targeting
- Entropic pulling and direct clamping
- J-domain cochaperones
- Evolution of J-domain cochaperones
- Non-equilibrium temperatures
- Model for the temperature-dependent conversion between Hsp70 states
- 2020 single-molecule FRET approach
- Hsp60 is also an ATP-consuming chaperone
- ATP-dependent reversion of the misfolded state into the native state
- Urea-treated MDH at 37°C
- The presence of GroELS and ATP repopulates native species
- Summary
- “Sine Sole Sileo”
- Acknowledgments
Topics Covered
- The role of molecular chaperones
- Concept of polypeptide unfolding enzymes
- The RubisCO binding protein
- Molecular chaperones can proof-read the quality of protein folding
- structure and function of Hsp70
- The folding state of Hsp70 substrate
- Substrate targeting
- Entropic pulling
- J-domain cochaperones
Links
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External Links
Talk Citation
Goloubinoff, P. (2021, June 29). How can molecular chaperones repair damaged protein structures? [Video file]. In The Biomedical & Life Sciences Collection, Henry Stewart Talks. Retrieved October 4, 2024, from https://doi.org/10.69645/KWRS2146.Export Citation (RIS)
Publication History
Financial Disclosures
- Prof. Pierre Goloubinoff has not informed HSTalks of any commercial/financial relationship that it is appropriate to disclose.
A selection of talks on Biochemistry
Transcript
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0:00
My name is Pierre Goloubinoff from the University of Lausanne in Switzerland.
I'm going to talk about molecular chaperones in particular Hsp70 and Hsp60,
which can inject energy from ATP hydrolysis into the
non-equilibrium stabilization of stress-labile proteins.
0:19
We can start by asking: what is a molecular chaperone?
If we go to the dictionary and look for a very traditional definition of a chaperone,
it's 'an older lady who accompanies unmarried girls in public to implement
social distancing, thereby preventing improper associations with boys'.
That's the traditional vision of a chaperone.
John Ellis, in 1988, revived the term 'chaperone', and suggested that the
molecular chaperone is a protein that accompanies nascent or
stress-destabilized proteins to prevent improper association with other
proteins, and to prevent the formation of aggregates which may be toxic.
Of course, it's a free interpretation of what he said at the time,
but essentially in a nutshell, this is his message.
It was extrapolated from Laskey's invention of the term 'molecular chaperone', about histone chaperones.
I would say that since 2006, I prefer to define a molecular chaperone as:
'a protein that can proof-read protein structures. It can identify and correct abnormal misfolded protein structures.
Most chaperones can use the energy from ATP-hydrolysis to unfold and
thereby repair damaged protein structures and scavenge toxic aggregates.'
1:35
In a way, it's a machinery that can proof-read protein structure,
and indeed we can identify, in the life of a protein, different states.
Protein is born as an extended polypeptide with high free energy,
this is a free energy landscape, and it comes out of the ribosome like that.
Anfinsen has shown that it can fold spontaneously to the native state,
which is presumably more stable, and therefore with a lower free energy state.
But Anfinsen also noticed that a fraction of his artificially-unfolded proteins would
not get to the native state, and would reach a state like an insoluble aggregate.
This can also be obtained when you take the native protein and stress it,
for example, with heat shock, these would then convert into aggregates.
Once you are in this low free energy state of misfolded fibrillar
or aggregates, for example, it's very difficult to get out of them.
Not only are these proteins not functional, but they can lead to diseases,
we know now that the whole process of aging in mammals (at least in our case,
or in metazoans in general), is associated with protein misfolding
and the accumulation of misfolded species.
We suspect that it is the intermediate misfolded monomers that are the
most toxic to cells (neuronal cells), but the hallmark of these diseases is the
accumulation of fibrils and all kinds of protein deposits, which can even be infectious in the case of prions.