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The mutational landscape of a prion-like domain

Author

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  • Benedetta Bolognesi

    (Center for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology
    The Barcelona Institute of Science and Technology)

  • Andre J. Faure

    (Center for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology)

  • Mireia Seuma

    (Center for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology
    The Barcelona Institute of Science and Technology)

  • Jörn M. Schmiedel

    (Center for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology)

  • Gian Gaetano Tartaglia

    (Center for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology
    Universitat Pompeu Fabra (UPF)
    Institució Catalana de Recerca i Estudis Avançats (ICREA)
    Sapienza University of Rome)

  • Ben Lehner

    (Center for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology
    Universitat Pompeu Fabra (UPF)
    Institució Catalana de Recerca i Estudis Avançats (ICREA))

Abstract

Insoluble protein aggregates are the hallmarks of many neurodegenerative diseases. For example, aggregates of TDP-43 occur in nearly all cases of amyotrophic lateral sclerosis (ALS). However, whether aggregates cause cellular toxicity is still not clear, even in simpler cellular systems. We reasoned that deep mutagenesis might be a powerful approach to disentangle the relationship between aggregation and toxicity. We generated >50,000 mutations in the prion-like domain (PRD) of TDP-43 and quantified their toxicity in yeast cells. Surprisingly, mutations that increase hydrophobicity and aggregation strongly decrease toxicity. In contrast, toxic variants promote the formation of dynamic liquid-like condensates. Mutations have their strongest effects in a hotspot that genetic interactions reveal to be structured in vivo, illustrating how mutagenesis can probe the in vivo structures of unstructured proteins. Our results show that aggregation of TDP-43 is not harmful but protects cells, most likely by titrating the protein away from a toxic liquid-like phase.

Suggested Citation

  • Benedetta Bolognesi & Andre J. Faure & Mireia Seuma & Jörn M. Schmiedel & Gian Gaetano Tartaglia & Ben Lehner, 2019. "The mutational landscape of a prion-like domain," Nature Communications, Nature, vol. 10(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-12101-z
    DOI: 10.1038/s41467-019-12101-z
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    Cited by:

    1. Takahiro Nemoto & Tommaso Ocari & Arthur Planul & Muge Tekinsoy & Emilia A. Zin & Deniz Dalkara & Ulisse Ferrari, 2023. "ACIDES: on-line monitoring of forward genetic screens for protein engineering," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    2. Rosa Antón & Miguel Á. Treviño & David Pantoja-Uceda & Sara Félix & María Babu & Eurico J. Cabrita & Markus Zweckstetter & Philip Tinnefeld & Andrés M. Vera & Javier Oroz, 2024. "Alternative low-populated conformations prompt phase transitions in polyalanine repeat expansions," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    3. Mireia Seuma & Ben Lehner & Benedetta Bolognesi, 2022. "An atlas of amyloid aggregation: the impact of substitutions, insertions, deletions and truncations on amyloid beta fibril nucleation," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    4. Jaime Carrasco & Rosa Antón & Alejandro Valbuena & David Pantoja-Uceda & Mayur Mukhi & Rubén Hervás & Douglas V. Laurents & María Gasset & Javier Oroz, 2023. "Metamorphism in TDP-43 prion-like domain determines chaperone recognition," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

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