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Ribosome inhibition by C9ORF72-ALS/FTD-associated poly-PR and poly-GR proteins revealed by cryo-EM [preprint]

Loveland, Anna B.
Svidritskiy, Egor
Susorov, Denis
Lee, Soojin
Park, Alexander
Demo, Gabriel
Gao, Fen-Biao
Korostelev, Andrei A.
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Abstract

Toxic dipeptide repeat (DPR) proteins are produced from expanded G4C2 hexanucleotide repeats in the C9ORF72 gene, which cause 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 cryo-EM structures reveal that poly-PR and poly-GR block the polypeptide tunnel of the ribosome, extending into the peptidyl-transferase center. Consistent with these findings, the macrolide erythromycin, which binds in the tunnel, competes with the DPR proteins 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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bioRxiv 2020.08.30.274597; doi: https://doi.org/10.1101/2020.08.30.274597. Link to preprint on bioRxiv.

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10.1101/2020.08.30.274597
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This article is a preprint. Preprints are preliminary reports of work that have not been certified by peer review.

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Now published in Nature Communications, doi:10.1038/s41467-022-30418-0

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.