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

Daniel Gestaut, Soung Hun Roh, Boxue Ma, Grigore Pintilie, Lukasz A. Joachimiak, Alexander Leitner, Thomas Walzthoeni, Ruedi Aebersold, Wah Chiu, Judith Frydman

Research output: Contribution to journalArticle

10 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)751-765.e15
JournalCell
Volume177
Issue number3
DOIs
StatePublished - Apr 18 2019

Keywords

  • CCT
  • GIMc
  • TRiC
  • XL-MS
  • chaperone
  • chaperonin
  • cryo-EM
  • prefoldin
  • proteostasis

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Gestaut, D., Roh, S. H., Ma, B., Pintilie, G., Joachimiak, L. A., Leitner, A., Walzthoeni, T., Aebersold, R., Chiu, W., & Frydman, J. (2019). The Chaperonin TRiC/CCT Associates with Prefoldin through a Conserved Electrostatic Interface Essential for Cellular Proteostasis. Cell, 177(3), 751-765.e15. https://doi.org/10.1016/j.cell.2019.03.012