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Understanding the physical determinants of pressure denaturation: Temperature switches the pressure-induced unfolding pathway

Roumestand, C.; Foldeners Dudas, E.; Puglisi, R.; Calio, A.; Barthe, P.; Temussi, P. A.; Pastore, A.

2024-07-17 biophysics
10.1101/2024.07.15.603545 bioRxiv
Show abstract

Proteins unfold under different environmental insults, among which are heat, cold, high pressure and chaotropic agents. Understanding the mechanisms that determine unfolding under each of these conditions is an important problem that directly relates to the physical forces that determine the three-dimensional structure of a protein. Here, we studied a residue-specific description of the unfolding transitions of the marginally stable yeast protein Yfh1 using high-pressure nuclear magnetic resonance. We compared the cold, heat and pressure unfolded states and demonstrated what has up to now been only a hypothesis: the pressure-unfolded spectrum shares features in common with that at low but not at high temperature and room pressure, suggesting a tighter similarity of the mechanisms and a similar role of hydration in these two processes. By exploring the phase diagram of the protein and mapping unfolding onto the three-dimensional structure of the protein, we also show that the pressure-induced unfolding pathways at low and high temperatures differ, suggesting a synergic mechanism between pressure- and temperature-induced denaturation. Our observations help us to reconstruct the structural events determining unfolding and distinguish the mechanisms that rule the different processes of unfolding.

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