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| Title | In situ analysis reveals the TRiC duty cycle and PDCD5 as an open-state cofactor. |
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| Journal, issue, pages | Nature, Vol. 637, Issue 8047, Page 983-990, Year 2025 |
| Publish date | Dec 11, 2024 |
 Authors | Huaipeng Xing / Remus R E Rosenkranz / Piere Rodriguez-Aliaga / Ting-Ting Lee / Tomáš Majtner / Stefanie Böhm / Beata Turoňová / Judith Frydman / Martin Beck /   |
| PubMed 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 ...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 homeostasis. Its dysfunction is related to cancer and neurodegenerative disease. 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. |
 External links | Nature / PubMed:39663456 / PubMed Central |
| Methods | EM (subtomogram averaging) |
| Resolution | 7.1 - 31.3 Å |
| Structure data |  EMDB-18913: Closed TRiC in human cells (untreated and treated)  EMDB-18914: Closed TRiC (D8 symmetry) in human cells (untreated and treated)  EMDB-18921: Open TRiC in human cells (untreated and treated)  EMDB-18922: Human open TRiC in untreated cells  EMDB-18923: Human open TRiC without PFD in untreated cells  EMDB-18924: Human open TRiC with one PFD in untreated cells  EMDB-18925: Human open TRiC with two PFDs in untreated cells  EMDB-18926: Human closed TRiC in untreated cells  EMDB-18927: Human closed TRiC (D8 symmetry) in untreated cells  EMDB-18928: Human closed TRiC (class 1) in untreated cells  EMDB-18929: Human closed TRiC (class 2) in untreated cells  EMDB-18930: Human closed TRiC (class 3) in untreated cells  EMDB-18931: Human open TRiC in HHT-treated cells  EMDB-18932: Human open TRiC without PFD in HHT-treated cells  EMDB-18933: Human open TRiC with one PFD in HHT-treated cells  EMDB-18934: Human open TRiC with two PFDs in HHT-treated cells  EMDB-18936: Human closed TRiC in HHT-treated cells  EMDB-18937: Human closed TRiC (D8 symmetry) in HHT-treated cells  EMDB-18938: Human closed TRiC (class 1) in HHT-treated cells  EMDB-18939: Human closed TRiC (class 2) in HHT-treated cells  EMDB-18940: Human closed TRiC (class 3) in HHT-treated cells |
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Homo sapiens (human)