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

Xing, H., Rosenkranz, R. R. E., Rodriguez-Aliaga, P., Lee, T.-T., Majtner, T., Böhm, S., et al. (2024). In situ analysis reveals the TRiC duty cycle and PDCD5 as an open-state cofactor. Nature. doi:10.1038/s41586-024-08321-z.

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 Creators:
Xing, Huaipeng1, 2, Author                 
Rosenkranz, Remus R. E.1, Author                 
Rodriguez-Aliaga, Piere3, Author
Lee, Ting-Ting3, Author
Majtner, Tomáš1, Author                 
Böhm, Stefanie1, Author                 
Turoňová, Beata1, Author                 
Frydman, Judith3, Author
Beck, Martin1, 4, Author                 
Affiliations:
1Department of Molecular Sociology, Max Planck Institute of Biophysics, Max Planck Society, ou_3040395              
2Faculty of Biochemistry, Chemistry and Pharmacy, Goethe University Frankfurt am Main, Frankfurt, Germany, ou_persistent22              
3Department of Biology and Genetics, Stanford University, Stanford, CA, USA, ou_persistent22              
4Institute of Biochemistry, Goethe University Frankfurt, Frankfurt, Germany, ou_persistent22              

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 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.

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Language(s): eng - English
 Dates: 2024-02-122024-10-292024-12-11
 Publication Status: Published online
 Pages: 8
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 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1038/s41586-024-08321-z
BibTex Citekey: xing_situ_2024
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Title: Nature
  Abbreviation : Nature
Source Genre: Journal
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Publ. Info: London : Nature Publishing Group
Pages: - Volume / Issue: - Sequence Number: - Start / End Page: - Identifier: ISSN: 0028-0836
CoNE: https://pure.mpg.de/cone/journals/resource/954925427238