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Lookup NU author(s): Professor Wyatt YueORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2022, The Author(s). The integrity of a cell’s proteome depends on correct folding of polypeptides by chaperonins. The chaperonin TCP-1 ring complex (TRiC) acts as obligate folder for >10% of cytosolic proteins, including he cytoskeletal proteins actin and tubulin. Although its architecture and how it recognizes folding substrates are emerging from structural studies, the subsequent fate of substrates inside the TRiC chamber is not defined. We trapped endogenous human TRiC with substrates (actin, tubulin) and cochaperone (PhLP2A) at different folding stages, for structure determination by cryo-EM. The already-folded regions of client proteins are anchored at the chamber wall, positioning unstructured regions toward the central space to achieve their native fold. Substrates engage with different sections of the chamber during the folding cycle, coupled to TRiC open-and-close transitions. Further, the cochaperone PhLP2A modulates folding, acting as a molecular strut between substrate and TRiC chamber. Our structural snapshots piece together an emerging model of client protein folding within TRiC.
Author(s): Kelly JJ, Tranter D, Pardon E, Chi G, Kramer H, Happonen L, Knee KM, Janz JM, Steyaert J, Bulawa C, Paavilainen VO, Huiskonen JT, Yue WW
Publication type: Article
Publication status: Published
Journal: Nature Structural and Molecular Biology
Year: 2022
Volume: 29
Issue: 5
Pages: 420-429
Print publication date: 01/05/2022
Online publication date: 21/04/2022
Acceptance date: 01/03/2022
Date deposited: 12/09/2024
ISSN (print): 1545-9993
ISSN (electronic): 1545-9985
Publisher: Nature Research
URL: https://doi.org/10.1038/s41594-022-00755-1
DOI: 10.1038/s41594-022-00755-1
Data Access Statement: Data sets generated during the current study are available from the Protein Data Bank (PDB) accession codes 7NVL, 7NVM, 7NVN, and 7NVO, and Electron Microscopy Data Bank (EMDB) accession codes EMD-12605, EMD-12606, EMD-12607, EMD-12608, and EMD-13754. All main data supporting the findings of this study are available within the article, Extended Data, and Supplementary Information. Source data are provided with this paper. Other data are available from the corresponding author upon reasonable request. Source data are provided with this paper.
PubMed id: 35449234
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