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

Author

Listed:
  • Anna B. Loveland

    (UMass Chan Medical School)

  • Egor Svidritskiy

    (UMass Chan Medical School)

  • Denis Susorov

    (UMass Chan Medical School)

  • Soojin Lee

    (UMass Chan Medical School)

  • Alexander Park

    (UMass Chan Medical School)

  • Sarah Zvornicanin

    (UMass Chan Medical School)

  • Gabriel Demo

    (UMass Chan Medical School
    Masaryk University)

  • Fen-Biao Gao

    (UMass Chan Medical School)

  • Andrei A. Korostelev

    (UMass Chan Medical School)

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.

Suggested Citation

  • Anna B. Loveland & Egor Svidritskiy & Denis Susorov & Soojin Lee & Alexander Park & Sarah Zvornicanin & Gabriel Demo & Fen-Biao Gao & Andrei A. Korostelev, 2022. "Ribosome inhibition by C9ORF72-ALS/FTD-associated poly-PR and poly-GR proteins revealed by cryo-EM," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30418-0
    DOI: 10.1038/s41467-022-30418-0
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    References listed on IDEAS

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    1. Ivan B. Lomakin & Thomas A. Steitz, 2013. "The initiation of mammalian protein synthesis and mRNA scanning mechanism," Nature, Nature, vol. 500(7462), pages 307-311, August.
    2. Nicolas Garreau de Loubresse & Irina Prokhorova & Wolf Holtkamp & Marina V. Rodnina & Gulnara Yusupova & Marat Yusupov, 2014. "Structural basis for the inhibition of the eukaryotic ribosome," Nature, Nature, vol. 513(7519), pages 517-522, September.
    3. Shaopeng Wang & Malgorzata J. Latallo & Zhe Zhang & Bo Huang & Dmitriy G. Bobrovnikov & Daoyuan Dong & Nathan M. Livingston & Wilson Tjoeng & Lindsey R. Hayes & Jeffrey D. Rothstein & Lyle W. Ostrow &, 2021. "Nuclear export and translation of circular repeat-containing intronic RNA in C9ORF72-ALS/FTD," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
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    1. Sammy Villa & Pankaj Dwivedi & Aaron Stahl & Trent Hinkle & Christopher M. Rose & Donald S. Kirkpatrick & Seth M. Tomchik & Vishva M. Dixit & Fred W. Wolf, 2024. "OTUD6 deubiquitination of RPS7/eS7 on the free 40 S ribosome regulates global protein translation and stress," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    2. Simon M. Lauer & Maren Reepmeyer & Ole Berendes & Dorota Klepacki & Jakob Gasse & Sara Gabrielli & Helmut Grubmüller & Lars V. Bock & Andor Krizsan & Rainer Nikolay & Christian M. T. Spahn & Ralf Hoff, 2024. "Multimodal binding and inhibition of bacterial ribosomes by the antimicrobial peptides Api137 and Api88," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    3. Phillip C. Burke & Heungwon Park & Arvind Rasi Subramaniam, 2022. "A nascent peptide code for translational control of mRNA stability in human cells," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    4. Malgorzata J. Latallo & Shaopeng Wang & Daoyuan Dong & Blake Nelson & Nathan M. Livingston & Rong Wu & Ning Zhao & Timothy J. Stasevich & Michael C. Bassik & Shuying Sun & Bin Wu, 2023. "Single-molecule imaging reveals distinct elongation and frameshifting dynamics between frames of expanded RNA repeats in C9ORF72-ALS/FTD," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    5. Antonios Apostolopoulos & Naohiro Kawamoto & Siu Yu A. Chow & Hitomi Tsuiji & Yoshiho Ikeuchi & Yuichi Shichino & Shintaro Iwasaki, 2024. "dCas13-mediated translational repression for accurate gene silencing in mammalian cells," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    6. Pavel V. Panteleev & Eugene B. Pichkur & Roman N. Kruglikov & Alena Paleskava & Olga V. Shulenina & Ilia A. Bolosov & Ivan V. Bogdanov & Victoria N. Safronova & Sergey V. Balandin & Valeriya I. Marina, 2024. "Rumicidins are a family of mammalian host-defense peptides plugging the 70S ribosome exit tunnel," Nature Communications, Nature, vol. 15(1), pages 1-15, December.

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