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Snapshots of actin and tubulin folding inside the TRiC chaperonin

Kelly, John J. ; Tranter, Dale ; Pardon, Els ; Chi, Gamma ; Kramer, Holger ; Happonen, Lotta LU ; Knee, Kelly M. ; Janz, Jay M. ; Steyaert, Jan and Bulawa, Christine , et al. (2022) In Nature Structural and Molecular Biology 29(5). p.420-429
Abstract

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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Nature Structural and Molecular Biology
volume
29
issue
5
pages
420 - 429
publisher
Nature Publishing Group
external identifiers
  • pmid:35449234
  • scopus:85128696425
ISSN
1545-9993
DOI
10.1038/s41594-022-00755-1
language
English
LU publication?
yes
additional info
Publisher Copyright: © 2022, The Author(s).
id
27533743-ce96-4c2c-bb10-029823570c5c
date added to LUP
2022-05-14 15:24:11
date last changed
2025-03-26 12:32:57
@article{27533743-ce96-4c2c-bb10-029823570c5c,
  abstract     = {{<p>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 &gt;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.</p>}},
  author       = {{Kelly, John J. and Tranter, Dale and Pardon, Els and Chi, Gamma and Kramer, Holger and Happonen, Lotta and Knee, Kelly M. and Janz, Jay M. and Steyaert, Jan and Bulawa, Christine and Paavilainen, Ville O. and Huiskonen, Juha T. and Yue, Wyatt W.}},
  issn         = {{1545-9993}},
  language     = {{eng}},
  number       = {{5}},
  pages        = {{420--429}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Structural and Molecular Biology}},
  title        = {{Snapshots of actin and tubulin folding inside the TRiC chaperonin}},
  url          = {{http://dx.doi.org/10.1038/s41594-022-00755-1}},
  doi          = {{10.1038/s41594-022-00755-1}},
  volume       = {{29}},
  year         = {{2022}},
}