Non-Equilibrium Protein Folding and Activation by ATP-Driven Chaperones
1Roivant Sciences, New York, NY 10036, USA.
Biomolecules
|June 24, 2022
Summary
ATP-driven molecular chaperones enable non-equilibrium protein folding by breaking symmetry conditions. This process allows some proteins to achieve thermodynamically unstable native states, challenging traditional folding hypotheses.
Area of Science:
- Biochemistry
- Molecular Biology
- Biophysics
Background:
- Experimental studies indicate ATP-driven molecular chaperones stabilize proteins out of thermal equilibrium.
- The precise mechanism of this non-equilibrium protein folding remains unclear.
Purpose of the Study:
- To propose a unifying principle for converting chemical energy from ATP hydrolysis into protein folding energy.
- To elucidate the distinct mechanisms employed by Hsp70 and Hsp90 chaperones in non-equilibrium folding.
Main Methods:
- Analysis of existing structural and biochemical evidence.
- Theoretical derivation of an upper bound for non-equilibrium native concentration elevation.
Main Results:
- Non-equilibrium folding necessitates chaperones breaking at least one of four symmetry conditions.
- Hsp70 and Hsp90 chaperones utilize different symmetry-breaking mechanisms.
- Non-equilibrium folding is limited to slow-folding proteins with unstable intermediate conformations.
Conclusions:
- Proposes a novel principle for ATP-driven non-equilibrium protein folding.
- Challenges Anfinsen's hypothesis by suggesting proteins can achieve unstable native states.
- Highlights the influence of chaperone-mediated pathways on protein structure.
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