EMD-26035

Single-particle
3.1 Å
EMD-26035 Deposition: 24/01/2022
Map released: 25/05/2022
Last modified: 21/02/2024
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links

EMD-26035

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

EMD-26035

Single-particle
3.1 Å
EMD-26035 Deposition: 24/01/2022
Map released: 25/05/2022
Last modified: 21/02/2024
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Sample Organism: Oryctolagus cuniculus, Saccharomyces cerevisiae, Homo sapiens, Escherichia coli K-12
Sample: Mamalian 80S ribosome bound with the ALS/FTD-associated dipeptide repeat protein PR20
Fitted models: 7toq (Avg. Q-score: 0.362)

Deposition Authors: Loveland AB , Svidritskiy E, Susorov D, Lee S, Park A, Zvornicanin S, Demo G , Gao FB , Korostelev AA
Ribosome inhibition by C9ORF72-ALS/FTD-associated poly-PR and poly-GR proteins revealed by cryo-EM.
Loveland AB , Svidritskiy E, Susorov D, Lee S, Park A, Zvornicanin S, Demo G , Gao FB , Korostelev AA
(2022) Nat Commun , 13 , 2776 - 2776
PUBMED: 35589706
DOI: doi:10.1038/s41467-022-30418-0
ISSN: 2041-1723
Abstract:
Toxic dipeptide-repeat (DPR) proteins are produced from expanded G4C2 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.