In situ analysis reveals the TRiC duty cycle and PDCD5 as an open-state cofactor

Huaipeng Xing, Remus R. E. Rosenkranz, Piere Rodriguez-Aliaga, Ting-Ting Lee, Tomáš Majtner, Stefanie Böhm, Beata Turoňová, Judith Frydman () and Martin Beck ()
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Huaipeng Xing: Max Planck Institute of Biophysics
Remus R. E. Rosenkranz: Max Planck Institute of Biophysics
Piere Rodriguez-Aliaga: Stanford University
Ting-Ting Lee: Stanford University
Tomáš Majtner: Max Planck Institute of Biophysics
Stefanie Böhm: Max Planck Institute of Biophysics
Beata Turoňová: Max Planck Institute of Biophysics
Judith Frydman: Stanford University
Martin Beck: Max Planck Institute of Biophysics

Nature, 2025, vol. 637, issue 8047, 983-990

Abstract: Abstract The ring-shaped chaperonin T-complex protein ring complex (TRiC; also known as chaperonin containing TCP-1, CCT) is an ATP-driven protein-folding machine that is essential for maintenance of cellular homeostasis1,2. Its dysfunction is related to cancer and neurodegenerative disease3,4. Despite its importance, how TRiC works in the cell remains unclear. Here we structurally analysed the architecture, conformational dynamics and spatial organization of the chaperonin TRiC in human cells using cryo-electron tomography. We resolved distinctive open, closed, substrate-bound and prefoldin-associated states of TRiC, and reconstructed its duty cycle in situ. The substrate-bound open and symmetrically closed TRiC states were equally abundant. Closed TRiC containing substrate forms distinctive clusters, indicative of spatial organization. Translation inhibition did not fundamentally change the distribution of duty cycle intermediates, but reduced substrate binding for all states as well as cluster formation. From our in-cell structures, we identified the programmed cell death protein 5 (PDCD5) as an interactor that specifically binds to almost all open but not closed TRiC, in a position that is compatible with both substrate and prefoldin binding. Our data support a model in which TRiC functions at near full occupancy to fold newly synthesized proteins inside cells. Defining the TRiC cycle and function inside cells lays the foundation to understand its dysfunction during cancer and neurodegeneration.

Date: 2025
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DOI: 10.1038/s41586-024-08321-z

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