RQC2 is a major player in peptide release from stalled ribosomes

Structure. 2025 Jun 5;33(6):1112-1121.e5. doi: 10.1016/j.str.2025.03.008. Epub 2025 Apr 4.

Abstract

Eukaryotic cells prevent the accumulation of potentially toxic aberrant polypeptides and maintain ribosome availability through surveillance and clearance mechanisms, including the evolutionarily conserved ribosome-associated quality control complex (RQC). RQC pathways have been widely investigated, with the identification of several factors ANKZF1/Vms1p, Ptrh1, and Arb1p involved in release/cleavage of the peptide-tRNA from 60S subunits. We aimed here to identify the genes involved in peptide release from stalled ribosomes. Using a genetic screen, we identified a mutant allele of RQC2 as involved in this process. We present the cryoelectron microscopy (cryo-EM) structure of RQC, which reveals how the F340I mutation affects mutant binding. This altered binding, in turn, disrupts the A-site's ability to bind the tRNA in the presence of Ltn1. These data account for the limitation of C-terminal alanine and threonine (CAT) tailing by the F340I mutation and suggest a model explaining the role of the Rqc2 protein in peptide release.

Keywords: No-Go decay; RNA stability; RQC2; nonstop decay; peptidyl-tRNA hydrolase; ribosome quality complex; yeast.

MeSH terms

  • Binding Sites
  • Cryoelectron Microscopy
  • Models, Molecular
  • Mutation
  • Peptides* / metabolism
  • Protein Binding
  • RNA, Transfer / chemistry
  • RNA, Transfer / metabolism
  • RNA-Binding Proteins* / chemistry
  • RNA-Binding Proteins* / genetics
  • RNA-Binding Proteins* / metabolism
  • Ribosomes* / chemistry
  • Ribosomes* / metabolism
  • Saccharomyces cerevisiae Proteins* / chemistry
  • Saccharomyces cerevisiae Proteins* / genetics
  • Saccharomyces cerevisiae Proteins* / metabolism
  • Saccharomyces cerevisiae* / genetics
  • Saccharomyces cerevisiae* / metabolism
  • Ubiquitin-Protein Ligases

Substances

  • Saccharomyces cerevisiae Proteins
  • Ltn1 protein, S cerevisiae
  • RNA, Transfer
  • Peptides
  • RNA-Binding Proteins
  • Ubiquitin-Protein Ligases