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Pharmacological perturbation of the phase-separating protein SMNDC1

Author

Listed:
  • Lennart Enders

    (CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences)

  • Marton Siklos

    (CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences)

  • Jan Borggräfe

    (Institute of Structural Biology
    Technical University of Munich, TUM School of Natural Sciences, Department of Bioscience, Bavarian NMR Center)

  • Stefan Gaussmann

    (Institute of Structural Biology
    Technical University of Munich, TUM School of Natural Sciences, Department of Bioscience, Bavarian NMR Center)

  • Anna Koren

    (CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences)

  • Monika Malik

    (CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences)

  • Tatjana Tomek

    (CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences)

  • Michael Schuster

    (CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences)

  • Jiří Reiniš

    (CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences)

  • Elisa Hahn

    (CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences)

  • Andrea Rukavina

    (CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences)

  • Andreas Reicher

    (CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences)

  • Tamara Casteels

    (CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
    Sloan Kettering Institute)

  • Christoph Bock

    (CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
    Medical University of Vienna, Institute of Artificial Intelligence, Center for Medical Data Science)

  • Georg E. Winter

    (CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences)

  • J. Thomas Hannich

    (CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences)

  • Michael Sattler

    (Institute of Structural Biology
    Technical University of Munich, TUM School of Natural Sciences, Department of Bioscience, Bavarian NMR Center)

  • Stefan Kubicek

    (CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences)

Abstract

SMNDC1 is a Tudor domain protein that recognizes di-methylated arginines and controls gene expression as an essential splicing factor. Here, we study the specific contributions of the SMNDC1 Tudor domain to protein-protein interactions, subcellular localization, and molecular function. To perturb the protein function in cells, we develop small molecule inhibitors targeting the dimethylarginine binding pocket of the SMNDC1 Tudor domain. We find that SMNDC1 localizes to phase-separated membraneless organelles that partially overlap with nuclear speckles. This condensation behavior is driven by the unstructured C-terminal region of SMNDC1, depends on RNA interaction and can be recapitulated in vitro. Inhibitors of the protein’s Tudor domain drastically alter protein-protein interactions and subcellular localization, causing splicing changes for SMNDC1-dependent genes. These compounds will enable further pharmacological studies on the role of SMNDC1 in the regulation of nuclear condensates, gene regulation and cell identity.

Suggested Citation

  • Lennart Enders & Marton Siklos & Jan Borggräfe & Stefan Gaussmann & Anna Koren & Monika Malik & Tatjana Tomek & Michael Schuster & Jiří Reiniš & Elisa Hahn & Andrea Rukavina & Andreas Reicher & Tamara, 2023. "Pharmacological perturbation of the phase-separating protein SMNDC1," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40124-0
    DOI: 10.1038/s41467-023-40124-0
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