한빛사 논문
Daniel Gestaut,1,10 Soung Hun Roh,2,10 Boxue Ma,3,10 Grigore Pintilie,2 Lukasz A. Joachimiak,1,4 Alexander Leitner,5 Thomas Walzthoeni,5,6,7 Ruedi Aebersold,5,8 Wah Chiu,9 and Judith Frydman1,11,*
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 Biochemistry, UTSouthwestern, North Campus, Dallas, TX 75390, USA
5 Institute of Molecular Systems Biology, Department of Biology, ETH Zurich, 8093 Zurich, Switzerland
6 PhD Program in Molecular Life Sciences, University of Zurich/ETH Zurich, 8057 Zurich, Switzerland
7 Institute of Computational Biology, Helmholtz Zentrum Munchen, 85764 Neuherberg, Germany
8 Faculty of Science, University of Zurich, Zurich, Switzerland
9 Department of Bioengineering, Stanford University, Stanford, CA 94305, USA
10 These authors contributed equally
11 Lead Contact
*Correspondence
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.
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