@article{fd28106d23b045b69a3deb03fccacf7c,
title = "The Chaperonin TRiC/CCT Associates with Prefoldin through a Conserved Electrostatic Interface Essential for Cellular Proteostasis",
abstract = "Maintaining proteostasis in eukaryotic protein folding involves cooperation of distinct chaperone systems. To understand how the essential ring-shaped chaperonin TRiC/CCT cooperates with the chaperone prefoldin/GIMc (PFD), we integrate cryoelectron microscopy (cryo-EM), crosslinking-mass-spectrometry and biochemical and cellular approaches to elucidate the structural and functional interplay between TRiC/CCT and PFD. We find these hetero-oligomeric chaperones associate in a defined architecture, through a conserved interface of electrostatic contacts that serves as a pivot point for a TRiC-PFD conformational cycle. PFD alternates between an open “latched” conformation and a closed “engaged” conformation that aligns the PFD-TRiC substrate binding chambers. PFD can act after TRiC bound its substrates to enhance the rate and yield of the folding reaction, suppressing non-productive reaction cycles. Disrupting the TRiC-PFD interaction in vivo is strongly deleterious, leading to accumulation of amyloid aggregates. The supra-chaperone assembly formed by PFD and TRiC is essential to prevent toxic conformations and ensure effective cellular proteostasis.",
keywords = "CCT, GIMc, TRiC, XL-MS, chaperone, chaperonin, cryo-EM, prefoldin, proteostasis",
author = "Daniel Gestaut and Roh, {Soung Hun} and Boxue Ma and Grigore Pintilie and Joachimiak, {Lukasz A.} and Alexander Leitner and Thomas Walzthoeni and Ruedi Aebersold and Wah Chiu and Judith Frydman",
note = "Funding Information: We thank P. Aliaga and K. Goncalves for help in yeast strain production; K. Rainbolt and R. Samant for advice on Proteostat staining; E. Sontag for help with fluorescence microscopy; R. Aviner; K. Li, and Al Burlingame for help with mass spectrometry; R. Andino and K. Dalton for discussions and comments on the manuscript; and the Frydman lab for useful advice and discussions. CryoEM data were collected at NCMI and processed at the CIBR at Baylor College of Medicine. This work was supported by NIH ( R01GM074074 to J.F., F32GM103124 to D.G., P41GM103832 and R01GM079429 to W.C., and P01NS092525 to W.C. and J.F.), the ERC ( AdvG #233226 and AdvG #670821 to R.A.), Seoul National University Settlement, and NRF ( 2019R1C1C004598 to S.H.R). Funding Information: We thank P. Aliaga and K. Goncalves for help in yeast strain production; K. Rainbolt and R. Samant for advice on Proteostat staining; E. Sontag for help with fluorescence microscopy; R. Aviner; K. Li, and Al Burlingame for help with mass spectrometry; R. Andino and K. Dalton for discussions and comments on the manuscript; and the Frydman lab for useful advice and discussions. CryoEM data were collected at NCMI and processed at the CIBR at Baylor College of Medicine. This work was supported by NIH (R01GM074074 to J.F. F32GM103124 to D.G. P41GM103832 and R01GM079429 to W.C. and P01NS092525 to W.C. and J.F.), the ERC (AdvG #233226 and AdvG #670821 to R.A.), Seoul National University Settlement, and NRF (2019R1C1C004598 to S.H.R). J.F. D.G. and W.C. conceived the project. D.G. carried out all biochemical experiments. B.M. collected and processed cryoEM data. S.H.R. carried out cryo-EM data analysis and structural modeling, assisted by G.P. D.G. L.A.J. A.L. and T.W. carried out the XL-MS experiments and analyses in the laboratory of R.A. D.G. carried out yeast work. D.G. S.H.R. and J.F. wrote the manuscript. All authors commented on the final version. J.F. directed the project. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",
year = "2019",
month = apr,
day = "18",
doi = "10.1016/j.cell.2019.03.012",
language = "English (US)",
volume = "177",
pages = "751--765.e15",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "3",
}