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Peptidyl-tRNA hydrolase is the nascent chain release factor in bacterial ribosome-associated quality control

Svetlov, Maxim S. ; Dunand, Clémence F. ; Nakamoto, Jose A. LU orcid ; Atkinson, Gemma C. LU ; Safdari, Haaris A. ; Wilson, Daniel N. ; Vázquez-Laslop, Nora and Mankin, Alexander S. (2024) In Molecular Cell 84(4). p.5-726
Abstract

Rescuing stalled ribosomes often involves their splitting into subunits. In many bacteria, the resultant large subunits bearing peptidyl-tRNAs are processed by the ribosome-associated quality control (RQC) apparatus that extends the C termini of the incomplete nascent polypeptides with polyalanine tails to facilitate their degradation. Although the tailing mechanism is well established, it is unclear how the nascent polypeptides are cleaved off the tRNAs. We show that peptidyl-tRNA hydrolase (Pth), the known role of which has been to hydrolyze ribosome-free peptidyl-tRNA, acts in concert with RQC factors to release nascent polypeptides from large ribosomal subunits. Dislodging from the ribosomal catalytic center is required for... (More)

Rescuing stalled ribosomes often involves their splitting into subunits. In many bacteria, the resultant large subunits bearing peptidyl-tRNAs are processed by the ribosome-associated quality control (RQC) apparatus that extends the C termini of the incomplete nascent polypeptides with polyalanine tails to facilitate their degradation. Although the tailing mechanism is well established, it is unclear how the nascent polypeptides are cleaved off the tRNAs. We show that peptidyl-tRNA hydrolase (Pth), the known role of which has been to hydrolyze ribosome-free peptidyl-tRNA, acts in concert with RQC factors to release nascent polypeptides from large ribosomal subunits. Dislodging from the ribosomal catalytic center is required for peptidyl-tRNA hydrolysis by Pth. Nascent protein folding may prevent peptidyl-tRNA retraction and interfere with the peptide release. However, oligoalanine tailing makes the peptidyl-tRNA ester bond accessible for Pth-catalyzed hydrolysis. Therefore, the oligoalanine tail serves not only as a degron but also as a facilitator of Pth-catalyzed peptidyl-tRNA hydrolysis.

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author
; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
alanine tailing, antibiotics, nascent peptide, protein folding, protein synthesis, ribosome rescue, translation
in
Molecular Cell
volume
84
issue
4
pages
5 - 726
publisher
Cell Press
external identifiers
  • pmid:38183984
  • scopus:85185348234
ISSN
1097-2765
DOI
10.1016/j.molcel.2023.12.002
language
English
LU publication?
yes
id
020e4d98-9ca1-428e-9d05-149ce87f1ccb
date added to LUP
2024-03-26 15:46:28
date last changed
2024-04-23 19:42:52
@article{020e4d98-9ca1-428e-9d05-149ce87f1ccb,
  abstract     = {{<p>Rescuing stalled ribosomes often involves their splitting into subunits. In many bacteria, the resultant large subunits bearing peptidyl-tRNAs are processed by the ribosome-associated quality control (RQC) apparatus that extends the C termini of the incomplete nascent polypeptides with polyalanine tails to facilitate their degradation. Although the tailing mechanism is well established, it is unclear how the nascent polypeptides are cleaved off the tRNAs. We show that peptidyl-tRNA hydrolase (Pth), the known role of which has been to hydrolyze ribosome-free peptidyl-tRNA, acts in concert with RQC factors to release nascent polypeptides from large ribosomal subunits. Dislodging from the ribosomal catalytic center is required for peptidyl-tRNA hydrolysis by Pth. Nascent protein folding may prevent peptidyl-tRNA retraction and interfere with the peptide release. However, oligoalanine tailing makes the peptidyl-tRNA ester bond accessible for Pth-catalyzed hydrolysis. Therefore, the oligoalanine tail serves not only as a degron but also as a facilitator of Pth-catalyzed peptidyl-tRNA hydrolysis.</p>}},
  author       = {{Svetlov, Maxim S. and Dunand, Clémence F. and Nakamoto, Jose A. and Atkinson, Gemma C. and Safdari, Haaris A. and Wilson, Daniel N. and Vázquez-Laslop, Nora and Mankin, Alexander S.}},
  issn         = {{1097-2765}},
  keywords     = {{alanine tailing; antibiotics; nascent peptide; protein folding; protein synthesis; ribosome rescue; translation}},
  language     = {{eng}},
  number       = {{4}},
  pages        = {{5--726}},
  publisher    = {{Cell Press}},
  series       = {{Molecular Cell}},
  title        = {{Peptidyl-tRNA hydrolase is the nascent chain release factor in bacterial ribosome-associated quality control}},
  url          = {{http://dx.doi.org/10.1016/j.molcel.2023.12.002}},
  doi          = {{10.1016/j.molcel.2023.12.002}},
  volume       = {{84}},
  year         = {{2024}},
}