The Chaperonin TRiC/CCT Associates with Prefoldin through a Conserved Electrostatic Interface Essential for Cellular Proteostasis

Gestaut, Daniel R.; Roh, Sook Young; Ma, Boxue; Pintilie, Grigore; Joachimiak, Łukasz A.; Leitner, Alexander; Walzthoeni, Thomas; Aebersold, Ruedi; Chiu, Wah; Frydman, Judith

doi:10.1016/j.cell.2019.03.012

Cited by 119 publications

(176 citation statements)

References 54 publications

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“…Our TRiC-PFD map shows that PFD can simultaneously bind both ends of TRiC in yeast ( SI Appendix , Fig. S10 C and D ); a similar phenomenon was also observed in bovine TRiC-human PFD (47), and human TRiC-PFD (human TRiC can bind 1 or 2 human PFDs depending on the concentration of PFD) (48). In summary, both rings of TRiC could potentially interact with the cochaperone for receiving delivered substrate at the same time.…”

Section: Discussionsupporting

confidence: 66%

An ensemble of cryo-EM structures of TRiC reveal its conformational landscape and subunit specificity

Jin

Han

Liu

et al. 2019

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

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TRiC/CCT assists the folding of ∼10% of cytosolic proteins through an ATP-driven conformational cycle and is essential in maintaining protein homeostasis. Here, we determined an ensemble of cryo-electron microscopy (cryo-EM) structures of yeast TRiC at various nucleotide concentrations, with 4 open-state maps resolved at near-atomic resolutions, and a closed-state map at atomic resolution, revealing an extra layer of an unforeseen N-terminal allosteric network. We found that, during TRiC ring closure, the CCT7 subunit moves first, responding to nucleotide binding; CCT4 is the last to bind ATP, serving as an ATP sensor; and CCT8 remains ADP-bound and is hardly involved in the ATPase-cycle in our experimental conditions; overall, yeast TRiC consumes nucleotide in a 2-ring positively coordinated manner. Our results depict a thorough picture of the TRiC conformational landscape and its allosteric transitions from the open to closed states in more structural detail and offer insights into TRiC subunit specificity in ATP consumption and ring closure, and potentially in substrate processing.

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Section: Discussionsupporting

confidence: 66%

An ensemble of cryo-EM structures of TRiC reveal its conformational landscape and subunit specificity

Jin

Han

Liu

et al. 2019

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

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“…Interestingly, PFD3, a subunit of the hexameric cochaperone prefoldin interacting with CCT ( Martín-Benito et al. 2002 ; Gestaut et al. 2019 ), was positively selected in two families (Amphiuridae: MNM, MEME, and BUSTED; Ophiodermatidae: MNM, aBSREL, MEME, and BUSTED) ( table 1 ; supplementary tables S2 and S6 , Supplementary Material online; fig.…”

Section: Resultsmentioning

confidence: 99%

Convergent Evolution and Structural Adaptation to the Deep Ocean in the Protein-Folding Chaperonin CCTα

Weber

Hugall

O’Hara

2020

Genome Biology and Evolution

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The deep ocean is the largest biome on Earth and yet it is among the least studied environments of our planet. Life at great depths requires several specific adaptations, however their molecular mechanisms remain understudied. We examined patterns of positive selection in 416 genes from four brittle star (Ophiuroidea) families displaying replicated events of deep-sea colonization (288 individuals from 216 species). We found consistent signatures of molecular convergence in functions related to protein biogenesis, including protein folding and translation. Five genes were recurrently positively selected, including CCTα (Chaperonin Containing TCP-1 subunit α), which is essential for protein folding. Molecular convergence was detected at the functional and gene levels but not at the amino-acid level. Pressure-adapted proteins are expected to display higher stability to counteract the effects of denaturation. We thus examined in silico local protein stability of CCTα across the ophiuroid tree of life (967 individuals from 725 species) in a phylogenetically-corrected context and found that deep sea-adapted proteins display higher stability within and next to the substrate-binding region, which was confirmed by in silico global protein stability analyses. This suggests that CCTα not only displays structural but also functional adaptations to deep water conditions. The CCT complex is involved in the folding of ∼10% of newly synthesized proteins and has previously been categorized as ‘cold-shock’ protein in numerous eukaryotes. We thus propose that adaptation mechanisms to cold and deep-sea environments may be linked and highlight that efficient protein biogenesis, including protein folding and translation, are key metabolic deep-sea adaptations.

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“…1,11 If disrupting the PFDN-c-CPN interaction in the body, it will be very harmful and will lead to the accumulation of amyloid aggregates, so this system is essential to prevent toxic conformations and ensure effective cellular protein stability. 14 PFDN can stabilize many nonnative proteins and prevent aggregation. When a subunit of the complex is deleted, it can cause cytoskeletal defects and protein aggregation.…”

Section: The Function Of Prefoldin To Maintain Protein Homeostasis Anmentioning

confidence: 99%

<p>The Role of Prefoldin and Its Subunits in Tumors and Their Application Prospects in Nanomedicine</p>

Mo¹,

Zhao²,

Tian³

et al. 2020

CMAR

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Prefoldin (PFDN) is a hexameric chaperone complex that is widely found in eukaryotes and archaea and consists of six different subunits (PFDN1-6). Its main function is to transfer actin and tubulin monomers to the eukaryotic cell cytoplasmic chaperone protein (c-CPN) specific binding during the assembly of the cytoskeleton, to stabilize the newly synthesized peptides so that they can be folded correctly. The current study found that each subunit of PFDN has different functions, which are closely related to the occurrence, development and prognosis of tumors. However, the best characteristics of each subunit have not been fully affirmed. The connection between research and tumors can change the understanding of PFDN and further extend its potential prognostic role and structural function to cancer research and clinical practice. This article mainly reviews the role of canonical PFDN and its subunits in tumors and other diseases, and discusses the potential prospects of the unique structure and function of PFDN in nanomedicine.

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The Chaperonin TRiC/CCT Associates with Prefoldin through a Conserved Electrostatic Interface Essential for Cellular Proteostasis

Cited by 119 publications

References 54 publications

An ensemble of cryo-EM structures of TRiC reveal its conformational landscape and subunit specificity

An ensemble of cryo-EM structures of TRiC reveal its conformational landscape and subunit specificity

Convergent Evolution and Structural Adaptation to the Deep Ocean in the Protein-Folding Chaperonin CCTα

<p>The Role of Prefoldin and Its Subunits in Tumors and Their Application Prospects in Nanomedicine</p>

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