LOVELAND, Anna B, Egor SVIDRITSKIY, Denis SUSOROV, Soojin LEE, Alexander PARK, Sarah ZVORNICANIN, Gabriel DEMO, Fen-Biao GAO and Andrei A KOROSTELEV. Ribosome inhibition by C9ORF72-ALS/FTD-associated poly-PR and poly-GR proteins revealed by cryo-EM. Nature Communications. London: Nature Publishing Group, 2022, vol. 13, No 1, p. 2776-2788. ISSN 2041-1723. Available from: https://dx.doi.org/10.1038/s41467-022-30418-0.
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Basic information
Original name Ribosome inhibition by C9ORF72-ALS/FTD-associated poly-PR and poly-GR proteins revealed by cryo-EM
Authors LOVELAND, Anna B, Egor SVIDRITSKIY, Denis SUSOROV, Soojin LEE, Alexander PARK, Sarah ZVORNICANIN, Gabriel DEMO (703 Slovakia, guarantor, belonging to the institution), Fen-Biao GAO and Andrei A KOROSTELEV.
Edition Nature Communications, London, Nature Publishing Group, 2022, 2041-1723.
Other information
Original language English
Type of outcome Article in a journal
Field of Study 10608 Biochemistry and molecular biology
Country of publisher Germany
Confidentiality degree is not subject to a state or trade secret
WWW URL
Impact factor Impact factor: 16.600
RIV identification code RIV/00216224:14740/22:00127474
Organization unit Central European Institute of Technology
Doi http://dx.doi.org/10.1038/s41467-022-30418-0
UT WoS 000798347800050
Keywords in English Amyotrophic Lateral Sclerosis; C9orf72 Protein; Cryoelectron Microscopy; Dipeptides; Frontotemporal Dementia; Humans; Proteins; Ribosomes; Transferases
Tags rivok
Tags International impact, Reviewed
Changed by Changed by: Mgr. Pavla Foltynová, Ph.D., učo 106624. Changed: 16/12/2022 13:38.
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.
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