Helmholtz Gemeinschaft

Search
Browse
Statistics
Feeds

Charcot-Marie-Tooth mutation in glycyl-tRNA synthetase stalls ribosomes in a pre-accommodation state and activates integrated stress response

[thumbnail of Original Article]
Preview
PDF (Original Article) - Requires a PDF viewer such as GSview, Xpdf or Adobe Acrobat Reader
2MB
[thumbnail of Supplementary Data]
Preview
PDF (Supplementary Data) - Requires a PDF viewer such as GSview, Xpdf or Adobe Acrobat Reader
107kB

Item Type:Article
Title:Charcot-Marie-Tooth mutation in glycyl-tRNA synthetase stalls ribosomes in a pre-accommodation state and activates integrated stress response
Creators Name:Mendonsa, S., von Kuegelgen, N., Bujanic, L. and Chekulaeva, M.
Abstract:Toxic gain-of-function mutations in aminoacyl-tRNA synthetases cause a degeneration of peripheral motor and sensory axons, known as Charcot-Marie-Tooth (CMT) disease. While these mutations do not disrupt overall aminoacylation activity, they interfere with translation via an unknown mechanism. Here, we dissect the mechanism of function of CMT mutant glycyl-tRNA synthetase (CMT-GARS), using high-resolution ribosome profiling and reporter assays. We find that CMT-GARS mutants deplete the pool of glycyl-tRNA(Gly) available for translation and inhibit the first stage of elongation, the accommodation of glycyl-tRNA into the ribosomal A-site, which causes ribosomes to pause at glycine codons. Moreover, ribosome pausing activates a secondary repression mechanism at the level of translation initiation, by inducing the phosphorylation of the alpha subunit of eIF2 and the integrated stress response. Thus, CMT-GARS mutant triggers translational repression via two interconnected mechanisms, affecting both elongation and initiation of translation.
Keywords:Cell Line, Charcot-Marie-Tooth Disease, Eukaryotic Initiation Factor-2, Gain of Function Mutation, Gene Expression, Glycine, Glycine-tRNA Ligase, HEK293 Cells, Translational Peptide Chain Elongation, Translational Peptide Chain Initiation, Phosphorylation, Protein Biosynthesis, Gly Transfer RNA, Ribosomes / Metabolism
Source:Nucleic Acids Research
ISSN:0305-1048
Publisher:Oxford University Press
Volume:49
Number:17
Page Range:10007-10017
Date:27 September 2021
Official Publication:https://doi.org/10.1093/nar/gkab730
PubMed:View item in PubMed

Repository Staff Only: item control page

Downloads

Downloads per month over past year

Open Access
MDC Library