Repetitive Protein Unfolding by the trans Ring of the GroEL-GroES Chaperonin Complex Stimulates Folding

Lin, Zong; Puchalla, Jason; Shoup, Daniel; Rye, Hays S.

doi:10.1074/jbc.m113.480178

Cited by 31 publications

(64 citation statements)

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“…We also showed that GroEL assists Rubisco folding, at least in part, through two phases of multiple axis unfolding of the misfolded Rubisco monomer (21,23,36). In addition, we observed an encapsulation-dependent compaction of the Rubisco folding intermediate, hinting at the possibility of an active role for confinement inside the GroEL-GroES chamber (21,23,36). Work on Rubisco by others (37,39) also suggested that confinement of the Rubisco monomer alters the folding landscape of the protein.…”

mentioning

confidence: 54%

“…We previously demonstrated that Rubisco populates a kinetically trapped, misfolded monomer that is efficiently rescued by GroEL in the absence of aggregation (36). We also showed that GroEL assists Rubisco folding, at least in part, through two phases of multiple axis unfolding of the misfolded Rubisco monomer (21,23,36). In addition, we observed an encapsulation-dependent compaction of the Rubisco folding intermediate, hinting at the possibility of an active role for confinement inside the GroEL-GroES chamber (21,23,36).…”

mentioning

confidence: 82%

“…Folding intermediates that do not commit to their native states within the lifetime of the GroEL-GroES cis cavity and that cannot complete folding in free solution must be recaptured for another round of processing. Thus, under the biologically relevant conditions of steadystate ATP turnover, the GroEL-GroES machine proceeds through a highly dynamic reaction cycle, the timing of which is ultimately set by the rate of ATP hydrolysis (20,21,24,28).…”

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confidence: 99%

“…The formation of the GroEL-GroES folding cavity is a highly ordered process, in which binding of the non-native protein on the open trans ring of a GroEL-GroES complex is followed by the obligate binding of ATP and then GroES to the same ring (15, 20 -23). The encapsulated protein can persist and fold within the GroELGroES cavity for a brief period of ϳ5-25 s, depending on conditions (20,21,24). Hydrolysis of the ATP inside the GroELGroES cavity (the cis cavity) prepares the complex for disassembly upon binding of substrate protein and ATP to the second trans ring (20).…”

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confidence: 99%

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The C-terminal Tails of the Bacterial Chaperonin GroEL Stimulate Protein Folding by Directly Altering the Conformation of a Substrate Protein

Weaver

Rye

2014

Journal of Biological Chemistry

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Background: Chaperonins like GroEL-GroES are required for the folding of many proteins. Results: The GroEL C termini alter substrate protein conformation and accelerate folding. Conclusion: Optimal protein folding requires the partial unfolding of misfolded states, a process that involves the GroEL C terminus. Significance: Chaperonins can actively facilitate protein folding by altering the conformations of folding intermediates.

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confidence: 54%

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confidence: 82%

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confidence: 99%

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confidence: 99%

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The C-terminal Tails of the Bacterial Chaperonin GroEL Stimulate Protein Folding by Directly Altering the Conformation of a Substrate Protein

Weaver

Rye

2014

Journal of Biological Chemistry

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“…Suffice to note that most (>99%) of the SP molecules that emerge from the cage with each turnover remain unfolded, still recognizable by GroEL. More importantly the rapid turnover of the SP by the symmetric GroEL:GroES 2 complex creates repeated opportunities for work to be done by the chaperonin machine by unfolding the SP (28)(29)(30) or its surrogates (31). As we have proposed in the iterative annealing mechanism, the rate of chaperonin-assisted protein folding is related to the number of iterations per unit time (32), in contrast to the Anfinsen cage model, which places a premium on extending the residence time of the encapsulated SP (5,6,22,23).…”

Section: On the Lifetime Of Anfinsen's Cage In The Presence Of Substratementioning

confidence: 99%

Symmetric GroEL:GroES ₂ complexes are the protein-folding functional form of the chaperonin nanomachine

Yang¹,

Ye²,

Lorimer

2013

Proc. Natl. Acad. Sci. U.S.A.

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Using calibrated FRET, we show that the simultaneous occupancy of both rings of GroEL by ATP and GroES occurs, leading to the rapid formation of symmetric GroEL:GroES 2 "football" particles regardless of the presence or absence of substrate protein (SP). In the absence of SP, these symmetric particles revert to asymmetric GroEL:GroES 1 "bullet" particles. The breakage of GroES symmetry requires the stochastic hydrolysis of ATP and the breakage of nucleotide symmetry. These asymmetric particles are both persistent and dynamic; they turnover via the asymmetric cycle. When challenged with SP, however, they revert to symmetric particles within a second. In the presence of SP, the symmetric particles are also persistent and dynamic. They turn over via the symmetric cycle. Under these conditions, the stochastic hydrolysis of ATP and the breakage of nucleotide symmetry also occur within the ensemble of particles. However, on account of SP-catalyzed ADP/ATP exchange, GroES symmetry is rapidly restored. The residence time of both GroES and SP on functional GroEL is reduced to ∼1 s, enabling many more iterations than was previously believed possible, consistent with the iterative annealing mechanism. This result is inconsistent with currently accepted models. Using a foldable SP, we show that as the SP folds to the native state and the population of unfolded SP declines, the population of symmetric particles reverts to asymmetric particles in parallel, a result that is consistent with the former being the folding functional form.G roEL plays a central role in the function of the GroEL/ GroES nanomachine. It binds unfolded proteins, transiently encapsulates them under the GroES "lid," and then releases them to the external medium, this cycle of events being driven by the hydrolysis of ATP (1, 2). GroEL, however, consists of two heptameric rings, and some controversy has arisen as to whether each ring operates alternately via an asymmetric cycle or simultaneously via a symmetric cycle. In the former case, GroEL engages one GroES at a time and the predominant species is the asymmetric GroEL:GroES 1 "bullet" complex whereas, in the latter, symmetric GroEL:GroES 2 "football" particles predominate in the symmetric cycle (figure 9 in ref. 4) (3, 4). Nevertheless, the asymmetric cycle, championed by leading authorities (5, 6), has become the widely accepted model of chaperonin function, promulgated in recent textbooks (7, 8) despite much evidence (9-21) that assigns a role to the symmetric football particles. However, the involvement of these symmetric particles in chaperonin function has been questioned on the basis of three items of chaperonin dogma: (i) that the formation of symmetric GroEL:GroES 2 particles and polypeptide binding are mutually exclusive (22, 23); (ii) the belief that, because of negative cooperativity, "when one GroEL ring binds ATP, the other ring cannot also do so" (5); and (iii) that the chaperonin ATPase cycle turns over at the same rate in the presence of substrate protein as it does in its absence. Here...

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Recent advances in understanding catalysis of protein folding by molecular chaperones

2020

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Molecular chaperones are highly conserved proteins that promote proper folding of other proteins in vivo. Diverse chaperone systems assist de novo protein folding and trafficking, the assembly of oligomeric complexes, and recovery from stress‐induced unfolding. A fundamental function of molecular chaperones is to inhibit unproductive protein interactions by recognizing and protecting hydrophobic surfaces that are exposed during folding or following proteotoxic stress. Beyond this basic principle, it is now clear that chaperones can also actively and specifically accelerate folding reactions in an ATP‐dependent manner. We focus on the bacterial Hsp70 and chaperonin systems as paradigms, and review recent work that has advanced our understanding of how these chaperones act as catalysts of protein folding.

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Repetitive Protein Unfolding by the trans Ring of the GroEL-GroES Chaperonin Complex Stimulates Folding

Cited by 31 publications

References 60 publications

The C-terminal Tails of the Bacterial Chaperonin GroEL Stimulate Protein Folding by Directly Altering the Conformation of a Substrate Protein

The C-terminal Tails of the Bacterial Chaperonin GroEL Stimulate Protein Folding by Directly Altering the Conformation of a Substrate Protein

Symmetric GroEL:GroES ₂ complexes are the protein-folding functional form of the chaperonin nanomachine

Recent advances in understanding catalysis of protein folding by molecular chaperones

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Repetitive Protein Unfolding by the trans Ring of the GroEL-GroES Chaperonin Complex Stimulates Folding

Cited by 31 publications

References 60 publications

The C-terminal Tails of the Bacterial Chaperonin GroEL Stimulate Protein Folding by Directly Altering the Conformation of a Substrate Protein

The C-terminal Tails of the Bacterial Chaperonin GroEL Stimulate Protein Folding by Directly Altering the Conformation of a Substrate Protein

Symmetric GroEL:GroES 2 complexes are the protein-folding functional form of the chaperonin nanomachine

Recent advances in understanding catalysis of protein folding by molecular chaperones

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Symmetric GroEL:GroES ₂ complexes are the protein-folding functional form of the chaperonin nanomachine