2. Academic Validation
  3. The Chaperonin TRiC/CCT Associates with Prefoldin through a Conserved Electrostatic Interface Essential for Cellular Proteostasis

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

  • Cell. 2019 Apr 18;177(3):751-765.e15. doi: 10.1016/j.cell.2019.03.012.
Daniel Gestaut 1,  Soung Hun Roh 2,  Boxue Ma 3,  Grigore Pintilie 2,  Lukasz A Joachimiak 4,  Alexander Leitner 5,  Thomas Walzthoeni 6,  Ruedi Aebersold 7,  Wah Chiu 8,  Judith Frydman 9
Affiliations

Affiliations

  • 1 Department of Biology and Genetics, Stanford University, Stanford, CA 94305, USA.
  • 2 Department of Biological Science, Seoul National University, Seoul, South Korea.
  • 3 Baylor College of Medicine, Houston, TX 77030, USA.
  • 4 Department of Biology and Genetics, Stanford University, Stanford, CA 94305, USA; Department of Biochemistry, UTSouthwestern, North Campus, Dallas, TX 75390, USA.
  • 5 Institute of Molecular Systems Biology, Department of Biology, ETH Zurich, 8093 Zurich, Switzerland.
  • 6 Institute of Molecular Systems Biology, Department of Biology, ETH Zurich, 8093 Zurich, Switzerland; PhD Program in Molecular Life Sciences, University of Zurich/ETH Zurich, 8057 Zurich, Switzerland; Institute of Computational Biology, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
  • 7 Institute of Molecular Systems Biology, Department of Biology, ETH Zurich, 8093 Zurich, Switzerland; Faculty of Science, University of Zurich, Zurich, Switzerland.
  • 8 Department of Bioengineering, Stanford University, Stanford, CA 94305, USA.
  • 9 Department of Biology and Genetics, Stanford University, Stanford, CA 94305, USA. Electronic address: jfrydman@stanford.edu.
PMID: 30955883 DOI: 10.1016/j.cell.2019.03.012
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.

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