Measuring protein stability in the GroEL chaperonin cage reveals massive destabilization

Korobko, Ilia; Mazal, Hisham; Haran, Gilad; Horovitz, Amnon

doi:10.7554/elife.56511

Cited by 12 publications

(24 citation statements)

References 32 publications

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“…One explanation, favored in the earlier work, is that the favorable interaction of the SP with exposed residues in the interior wall of the expanded GroEL cavity , could increase the folding barrier. This would also imply that certain SPs are thermodynamically destabilized in the GroEL/ES cage not by interactions between the SP and the walls of the GroEL. Destabilization could occur because of alterations due to solvent-mediated interactions between hydrophobic residues in the SP in a confined environment.…”

Section: Results and Discussionmentioning

confidence: 99%

Retardation of Folding Rates of Substrate Proteins in the Nanocage of GroEL

Koculi

Thirumalai

2021

Biochemistry

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The Escherichia coli ATP-consuming chaperonin machinery, a complex between GroEL and GroES, has evolved to facilitate folding of substrate proteins (SPs) that cannot do so spontaneously. A series of kinetic experiments show that the SPs are encapsulated in the GroEL/ES nanocage for a short duration. If confinement of the SPs is the mechanism by which GroEL/ES facilitates folding, it follows that the assisted folding rate, relative to the bulk value, should always be enhanced. Here, we show that this is not the case for the folding of rhodanese in the presence of the full machinery of GroEL/ES and ATP. The assisted folding rate of rhodanese decreases. On the basis of our finding and those reported in other studies, we suggest that the ATPconsuming chaperonin machinery has evolved to optimize the product of the folding rate and the yield of the folded SPs on the biological time scale. Neither the rate nor the yield is separately maximized.

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Section: Results and Discussionmentioning

confidence: 99%

Retardation of Folding Rates of Substrate Proteins in the Nanocage of GroEL

Koculi

Thirumalai

2021

Biochemistry

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“…One explanation, favored in the earlier work 29 is that the favorable interaction of the SP with exposed residues 29 in the interior wall of the expanded GroEL cavity 18-19 could increase the folding barrier. This would also imply that certain SPs are thermodynamically destabilized in the GroEL/ES cage 38 . Regardless of the molecular mechanism, which is important to decipher, it is clear that GroEL/ES machinery has not evolved to enhance the folding rates of proteins but to maximize the yield, Y N , of the native material of the on biological time scales 12-13, 29, 39 .…”

Section: Resultsmentioning

confidence: 99%

Retardation of folding rates of substrate proteins in the nanocage of GroEL

Koculi

Thirumalai

2020

Preprint

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The E. Coli. ATP-consuming chaperonin machinery, a complex between GroEL and GroES, has evolved to facilitate folding of substrate proteins (SPs) that cannot do so spontaneously. A series of kinetic experiments show that the SPs are encapsulated in the GroEL/ES nano cage for a short duration. If confining the SPs in the predominantly polar cage of GroEL in order to help folding, the assisted folding rate, relative to the bulk value, should always be enhanced. Here, we show that this is not the case for the folding of rhodanese in the presence of the full machinery of GroEL/ES and ATP. The assisted folding rate of rhodanese decreases. Based on our finding and those reported in other studies, we suggest that the ATP-consuming chaperonin machinery has evolved to optimize the product of the folding rate and the yield of the folded SPs on the biological time scale. Neither the rate nor the yield is separately maximized.

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“…(i) Protein folding in the chamber can be accelerated by the confinement reducing conformational freedom [ 31 ]. (ii) The chamber can act as unfoldase (or destabilization) to resolve the kinetically trapped intermediate, giving a chance for protein to refold [ 32 ]. (iii) Protein folding occurs such as free in solution [ 33 ].…”

Section: Relationship Between Protein Folding and Aggregationmentioning

confidence: 99%

A Conceptual Framework for Integrating Cellular Protein Folding, Misfolding and Aggregation

Choi

Seong

2021

Life

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How proteins properly fold and maintain solubility at the risk of misfolding and aggregation in the cellular environments still remains largely unknown. Aggregation has been traditionally treated as a consequence of protein folding (or misfolding). Notably, however, aggregation can be generally inhibited by affecting the intermolecular interactions leading to aggregation, independently of protein folding and conformation. We here point out that rigorous distinction between protein folding and aggregation as two independent processes is necessary to reconcile and underlie all observations regarding the combined cellular protein folding and aggregation. So far, the direct attractive interactions (e.g., hydrophobic interactions) between cellular macromolecules including chaperones and interacting polypeptides have been widely believed to mainly stabilize polypeptides against aggregation. However, the intermolecular repulsions by large excluded volume and surface charges of cellular macromolecules can play a key role in stabilizing their physically connected polypeptides against aggregation, irrespective of the connection types and induced conformational changes, underlying the generic intrinsic chaperone activity of cellular macromolecules. Such rigorous distinction and intermolecular repulsive force-driven aggregation inhibition by cellular macromolecules could give new insights into understanding the complex cellular protein landscapes that remain uncharted.

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Measuring protein stability in the GroEL chaperonin cage reveals massive destabilization

Cited by 12 publications

References 32 publications

Retardation of Folding Rates of Substrate Proteins in the Nanocage of GroEL

Retardation of Folding Rates of Substrate Proteins in the Nanocage of GroEL

Retardation of folding rates of substrate proteins in the nanocage of GroEL

A Conceptual Framework for Integrating Cellular Protein Folding, Misfolding and Aggregation

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