Allosteric Mechanisms in Chaperonin Machines

Gruber, Ranit; Horovitz, Amnon

doi:10.1021/acs.chemrev.5b00556

Cited by 89 publications

(82 citation statements)

References 197 publications

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“…The apical domains form the entrance to the cavity and expose hydrophobic residues for the binding of a nonnative substrate protein. The two rings of GroEL function sequentially as folding chambers, regulated allosterically by the GroEL ATPase (83,84). Binding of ATP and GroES to the substratebound ring causes the displacement of the nonnative substrate from its hydrophobic attachment sites into a cavity capped by GroES (Fig.…”

Section: Chaperonins-nanocages For Protein Foldingmentioning

confidence: 99%

In vivo aspects of protein folding and quality control

Balchin

Hayer‐Hartl

Hartl

2016

Science

1,216

1,109

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Most proteins must fold into unique three-dimensional structures to perform their biological functions. In the crowded cellular environment, newly synthesized proteins are at risk of misfolding and forming toxic aggregate species. To ensure efficient folding, different classes of molecular chaperones receive the nascent protein chain emerging from the ribosome and guide it along a productive folding pathway. Because proteins are structurally dynamic, constant surveillance of the proteome by an integrated network of chaperones and protein degradation machineries is required to maintain protein homeostasis (proteostasis). The capacity of this proteostasis network declines during aging, facilitating neurodegeneration and other chronic diseases associated with protein aggregation. Understanding the proteostasis network holds the promise of identifying targets for pharmacological intervention in these pathologies.

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Section: Chaperonins-nanocages For Protein Foldingmentioning

confidence: 99%

In vivo aspects of protein folding and quality control

Balchin

Hayer‐Hartl

Hartl

2016

Science

1,216

1,109

View full text Add to dashboard Cite

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“…The oligomeric rings that form these machines usually consist of five to eight subunits that undergo coordinated conformational changes driven by ATP binding and/or hydrolysis. These conformational changes can take place in a concerted fashion as in the case of the chaperonin GroEL (4). Alternatively, they can also occur in a sequential or stochastic manner as reported, for example, for the CCT/TRiC chaperone complex (4) and ClpX (5), respectively.…”

mentioning

confidence: 95%

“…These conformational changes can take place in a concerted fashion as in the case of the chaperonin GroEL (4). Alternatively, they can also occur in a sequential or stochastic manner as reported, for example, for the CCT/TRiC chaperone complex (4) and ClpX (5), respectively. Knowing the mode of allosteric switching is essential for understanding the mechanism of action of biomolecular machines.…”

mentioning

confidence: 95%

Sequential allosteric mechanism of ATP hydrolysis by the CCT/TRiC chaperone is revealed through Arrhenius analysis

Gruber

Levitt

Horovitz

2017

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

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Knowing the mechanism of allosteric switching is important for understanding how molecular machines work. The CCT/TRiC chaperonin nanomachine undergoes ATP-driven conformational changes that are crucial for its folding function. Here, we demonstrate that insight into its allosteric mechanism of ATP hydrolysis can be achieved by Arrhenius analysis. Our results show that ATP hydrolysis triggers sequential "conformational waves." They also suggest that these waves start from subunits CCT6 and CCT8 (or CCT3 and CCT6) and proceed clockwise and counterclockwise, respectively.chaperonins | allostery | conformational changes | molecular machines A TP-fueled ring-shaped nanomachines are ubiquitous and found in all domains of life. Examples for such machines include chaperones that mediate protein folding and degradation (1), DNA and RNA remodeling enzymes (2), and proteins involved in intracellular trafficking (3). The oligomeric rings that form these machines usually consist of five to eight subunits that undergo coordinated conformational changes driven by ATP binding and/or hydrolysis. These conformational changes can take place in a concerted fashion as in the case of the chaperonin GroEL (4). Alternatively, they can also occur in a sequential or stochastic manner as reported, for example, for the CCT/TRiC chaperone complex (4) and ClpX (5), respectively. Knowing the mode of allosteric switching is essential for understanding the mechanism of action of biomolecular machines. Distinguishing between these different modes of allosteric switching can be achieved using native mass spectrometry (6, 7) and single-molecule fluorescence (8) and force-based (2) techniques but has been difficult to accomplish using traditional biochemical approaches. Here, we show that classical Arrhenius analysis can be used to unpick the allosteric mechanism of ATP hydrolysis by the CCT/ TRiC chaperone.CCT/TRiC is a member of group II chaperonins found in archaea and the eukaryotic cytosol that assist protein folding in an ATPdependent manner. Clients of this chaperonin system include β-actin, α-and β-tubulin, and several hundred other proteins (9, 10). CCT/TRiC consists of two identical back-to-back stacked octameric rings with a cavity at each end where protein folding can take place (11). Each ring of CCT/TRiC is made up of eight different subunits that are arranged in a fixed order around the ring. The correct order was established by determining which arrangement is most consistent with interresidue distance constraints obtained from chemical crosslinking and mass spectrometry (12). This order was also found to give the best fit to the crystallographic data for CCT/TRiC (9) and was, therefore, used to redetermine its structure accordingly (13). The eight subunits of CCT/TRiC have a similar structure that consists of three domains: (i) an apical domain that is involved in protein substrate binding, (ii) an equatorial domain that is involved in ring-ring interactions and contains an ATP binding site, and (iii) an intermediate domain that l...

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“…After client binding, ATP binding and hydrolysis trigger conformational changes in the apical domains that lower client affinity, releas- ing the client protein into the chamber. The chamber then closes, through binding the co-chaperone GroES (in the case of GroEL) or through conformational changes (in the case of TRiC) (21). Relatively slow ATP hydrolysis provides the client protein time to fold while trapped within the chamber (Fig.…”

Section: Hsp60mentioning

confidence: 99%