Is Protein Folding a Thermodynamically Unfavorable, Active, Energy-Dependent Process?

Sorokina, Irina; Mushegian, Arcady; Koonin, Eugene V.

doi:10.3390/ijms23010521

Cited by 30 publications

(29 citation statements)

References 183 publications

(187 reference statements)

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“…These results are consistent with the idea that the native structures of some proteins may be determined by kinetics rather than thermodynamics. One implication is that the solution to the structure prediction problem for such proteins in cell may depend on the solution to the protein folding problem, and in-cell protein folding may be an active, energy-dependent process [ 104 ]. Predicting the cellular conformation of these proteins—in the presence of ATP-driven chaperones—may require the search for folding pathways that limit the exposures of cochaperone-binding, e.g., hydrophobic, sites.…”

Section: Discussionmentioning

confidence: 99%

Non-Equilibrium Protein Folding and Activation by ATP-Driven Chaperones

2022

Biomolecules

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Recent experimental studies suggest that ATP-driven molecular chaperones can stabilize protein substrates in their native structures out of thermal equilibrium. The mechanism of such non-equilibrium protein folding is an open question. Based on available structural and biochemical evidence, I propose here a unifying principle that underlies the conversion of chemical energy from ATP hydrolysis to the conformational free energy associated with protein folding and activation. I demonstrate that non-equilibrium folding requires the chaperones to break at least one of four symmetry conditions. The Hsp70 and Hsp90 chaperones each break a different subset of these symmetries and thus they use different mechanisms for non-equilibrium protein folding. I derive an upper bound on the non-equilibrium elevation of the native concentration, which implies that non-equilibrium folding only occurs in slow-folding proteins that adopt an unstable intermediate conformation in binding to ATP-driven chaperones. Contrary to the long-held view of Anfinsen’s hypothesis that proteins fold to their conformational free energy minima, my results predict that some proteins may fold into thermodynamically unstable native structures with the assistance of ATP-driven chaperones, and that the native structures of some chaperone-dependent proteins may be shaped by their chaperone-mediated folding pathways.

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Section: Discussionmentioning

confidence: 99%

Non-Equilibrium Protein Folding and Activation by ATP-Driven Chaperones

2022

Biomolecules

View full text Add to dashboard Cite

show abstract

“…These results are consistent with the idea that the native structures of some proteins may be determined by kinetics rather than thermodynamics. One implication is that the solution to the structure prediction problem for such proteins in cell may depend on the solution to the protein folding problem, and in-cell protein folding may be an active, energy-dependent process [91]. Predicting the cellular conformation of these proteins—in the presence of ATP-driven chaperones—may require the search for folding pathways that limit the exposures of cochaperone-binding, e.g .…”

Section: Discussionmentioning

confidence: 99%

Non-equilibrium protein folding and activation by ATP-driven chaperones

2022

Preprint

View full text Add to dashboard Cite

Recent experimental studies suggest that ATP-driven molecular chaperones can stabilize protein substrates in their native structures out of thermal equilibrium. The mechanism of such non-equilibrium protein folding is an open question. Based on available structural and biochemical evidence, I propose here a unifying principle that underlies the conversion of chemical energy from ATP hydrolysis to the conformational free energy associated with protein folding and activation. I demonstrate that non-equilibrium folding requires the chaperones to break at least one of four symmetry conditions. The Hsp70 and Hsp90 chaperones each breaks a different subset of these symmetries and thus they use different mechanisms for non-equilibrium protein folding. I derive an upper bound on the non-equilibrium elevation of the native concentration, which implies that non-equilibrium folding only occurs in slow-folding proteins that adopt an unstable intermediate conformation in binding to ATP-driven chaperones. Contrary to the long-held view of Anfinsen's hypothesis that proteins fold to their conformational free energy minima, my results predict that some proteins may fold into thermodynamically unstable native structures with the assistance of ATP-driven chaperones, and that the native structures of some chaperone-dependent proteins may be shaped by their chaperone-mediated folding pathways.

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“…Thus, the article by Koonin [ 123 ] and the previous works of his co-authors [ 108 , 124 , 125 , 126 ] consider an alternative hypothesis of protein folding, the kinetic one, according to which the native conformation of most proteins is not in the global but rather at a local minimum in the fluctuating free energy landscape. Moreover, the free energy values are probably positive for most proteins, which implies the energy costs to adopt a native conformation, which is only possible as a result of the interaction of these proteins with the molecular machines of the cell, such as translation systems or chaperones.…”

Section: Mechanisms Of the Formation Of Misfolded Proteinsmentioning

confidence: 99%

Regulation by Different Types of Chaperones of Amyloid Transformation of Proteins Involved in the Development of Neurodegenerative Diseases

Muronetz

Kudryavtseva

Leisi

et al. 2022

IJMS

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The review highlights various aspects of the influence of chaperones on amyloid proteins associated with the development of neurodegenerative diseases and includes studies conducted in our laboratory. Different sections of the article are devoted to the role of chaperones in the pathological transformation of alpha-synuclein and the prion protein. Information about the interaction of the chaperonins GroE and TRiC as well as polymer-based artificial chaperones with amyloidogenic proteins is summarized. Particular attention is paid to the effect of blocking chaperones by misfolded and amyloidogenic proteins. It was noted that the accumulation of functionally inactive chaperones blocked by misfolded proteins might cause the formation of amyloid aggregates and prevent the disassembly of fibrillar structures. Moreover, the blocking of chaperones by various forms of amyloid proteins might lead to pathological changes in the vital activity of cells due to the impaired folding of newly synthesized proteins and their subsequent processing. The final section of the article discusses both the little data on the role of gut microbiota in the propagation of synucleinopathies and prion diseases and the possible involvement of the bacterial chaperone GroE in these processes.

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Is Protein Folding a Thermodynamically Unfavorable, Active, Energy-Dependent Process?

Cited by 30 publications

References 183 publications

Non-Equilibrium Protein Folding and Activation by ATP-Driven Chaperones

Non-Equilibrium Protein Folding and Activation by ATP-Driven Chaperones

Non-equilibrium protein folding and activation by ATP-driven chaperones

Regulation by Different Types of Chaperones of Amyloid Transformation of Proteins Involved in the Development of Neurodegenerative Diseases

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