7TOQ

Mammalian 80S ribosome bound with the ALS/FTD-associated dipeptide repeat protein poly-PR

This is a non-PDB format compatible entry.

Summary for 7TOQ

• Entry DOI: 10.2210/pdb7toq/pdb
• EMDB information: 26035
• Descriptor: 18S rRNA, uL30, eL8, ... (85 entities in total)
• Functional Keywords: ribosomal binding peptide, als/ftd-associated dipeptide repeat protein, ribosome
• Biological source: Oryctolagus cuniculus (rabbit); More
• Total number of polymer chains: 84
• Total formula weight: 3177725.45

Authors

Loveland, A.B.,Svidritskiy, E.,Susorov, D.,Lee, S.,Park, A.,Zvornicanin, S.,Demo, G.,Gao, F.B.,Korostelev, A.A. (deposition date: 2022-01-24, release date: 2022-05-25, Last modification date: 2024-02-21)

Primary citation

Loveland, A.B.,Svidritskiy, E.,Susorov, D.,Lee, S.,Park, A.,Zvornicanin, S.,Demo, G.,Gao, F.B.,Korostelev, A.A.
Ribosome inhibition by C9ORF72-ALS/FTD-associated poly-PR and poly-GR proteins revealed by cryo-EM.
Nat Commun, 13:2776-2776, 2022

PubMed Abstract: Toxic dipeptide-repeat (DPR) proteins are produced from expanded GC repeats in the C9ORF72 gene, the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Two DPR proteins, poly-PR and poly-GR, repress cellular translation but the molecular mechanism remains unknown. Here we show that poly-PR and poly-GR of ≥20 repeats inhibit the ribosome's peptidyl-transferase activity at nanomolar concentrations, comparable to specific translation inhibitors. High-resolution cryogenic electron microscopy (cryo-EM) reveals that poly-PR and poly-GR block the polypeptide tunnel of the ribosome, extending into the peptidyl-transferase center (PTC). Consistent with these findings, the macrolide erythromycin, which binds in the tunnel, competes with poly-PR and restores peptidyl-transferase activity. Our results demonstrate that strong and specific binding of poly-PR and poly-GR in the ribosomal tunnel blocks translation, revealing the structural basis of their toxicity in C9ORF72-ALS/FTD.

PubMed: 35589706
DOI: 10.1038/s41467-022-30418-0

Experimental method

ELECTRON MICROSCOPY (3.1 Å)