Structural visualization of the tubulin folding pathway directed by human chaperonin TRiC/CCT.
Cell
; 185(25): 4770-4787.e20, 2022 Dec 08.
Article
em En
| MEDLINE
| ID: mdl-36493755
ABSTRACT
The ATP-dependent ring-shaped chaperonin TRiC/CCT is essential for cellular proteostasis. To uncover why some eukaryotic proteins can only fold with TRiC assistance, we reconstituted the folding of ß-tubulin using human prefoldin and TRiC. We find unstructured ß-tubulin is delivered by prefoldin to the open TRiC chamber followed by ATP-dependent chamber closure. Cryo-EM resolves four near-atomic-resolution structures containing progressively folded ß-tubulin intermediates within the closed TRiC chamber, culminating in native tubulin. This substrate folding pathway appears closely guided by site-specific interactions with conserved regions in the TRiC chamber. Initial electrostatic interactions between the TRiC interior wall and both the folded tubulin N domain and its C-terminal E-hook tail establish the native substrate topology, thus enabling C-domain folding. Intrinsically disordered CCT C termini within the chamber promote subsequent folding of tubulin's core and middle domains and GTP-binding. Thus, TRiC's chamber provides chemical and topological directives that shape the folding landscape of its obligate substrates.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Tubulina (Proteína)
/
Chaperonina com TCP-1
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article