How can molecular chaperones repair damaged protein structures?

Published on June 29, 2021   44 min

Other Talks in the Category: Biochemistry

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.
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How can molecular chaperones repair damaged protein structures?

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