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Aggregating sequences that occur in many proteins constitute weak spots of bacterial proteostasis

Author

Listed:
  • Ladan Khodaparast

    (KULeuven
    VIB Center for Brain and Disease Research
    KULeuven)

  • Laleh Khodaparast

    (KULeuven
    VIB Center for Brain and Disease Research
    KULeuven)

  • Rodrigo Gallardo

    (VIB Center for Brain and Disease Research
    KULeuven)

  • Nikolaos N. Louros

    (VIB Center for Brain and Disease Research
    KULeuven)

  • Emiel Michiels

    (VIB Center for Brain and Disease Research
    KULeuven)

  • Reshmi Ramakrishnan

    (VIB Center for Brain and Disease Research
    KULeuven)

  • Meine Ramakers

    (VIB Center for Brain and Disease Research
    KULeuven)

  • Filip Claes

    (VIB Center for Brain and Disease Research
    KULeuven)

  • Lydia Young

    (University of Leeds
    University of Leeds)

  • Mohammad Shahrooei

    (KULeuven)

  • Hannah Wilkinson

    (VIB Center for Brain and Disease Research
    KULeuven)

  • Matyas Desager

    (VIB Center for Brain and Disease Research
    KULeuven)

  • Wubishet Mengistu Tadesse

    (KULeuven)

  • K. Peter R. Nilsson

    (Linköping University)

  • Per Hammarström

    (Linköping University)

  • Abram Aertsen

    (KULeuven)

  • Sebastien Carpentier

    (KULeuven)

  • Johan Eldere

    (KULeuven)

  • Frederic Rousseau

    (VIB Center for Brain and Disease Research
    KULeuven)

  • Joost Schymkowitz

    (VIB Center for Brain and Disease Research
    KULeuven)

Abstract

Aggregation is a sequence-specific process, nucleated by short aggregation-prone regions (APRs) that can be exploited to induce aggregation of proteins containing the same APR. Here, we find that most APRs are unique within a proteome, but that a small minority of APRs occur in many proteins. When aggregation is nucleated in bacteria by such frequently occurring APRs, it leads to massive and lethal inclusion body formation containing a large number of proteins. Buildup of bacterial resistance against these peptides is slow. In addition, the approach is effective against drug-resistant clinical isolates of Escherichia coli and Acinetobacter baumannii, reducing bacterial load in a murine bladder infection model. Our results indicate that redundant APRs are weak points of bacterial protein homeostasis and that targeting these may be an attractive antibacterial strategy.

Suggested Citation

  • Ladan Khodaparast & Laleh Khodaparast & Rodrigo Gallardo & Nikolaos N. Louros & Emiel Michiels & Reshmi Ramakrishnan & Meine Ramakers & Filip Claes & Lydia Young & Mohammad Shahrooei & Hannah Wilkinso, 2018. "Aggregating sequences that occur in many proteins constitute weak spots of bacterial proteostasis," Nature Communications, Nature, vol. 9(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-03131-0
    DOI: 10.1038/s41467-018-03131-0
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    Cited by:

    1. Nikolaos Louros & Meine Ramakers & Emiel Michiels & Katerina Konstantoulea & Chiara Morelli & Teresa Garcia & Nele Moonen & Sam D’Haeyer & Vera Goossens & Dietmar Rudolf Thal & Dominique Audenaert & F, 2022. "Mapping the sequence specificity of heterotypic amyloid interactions enables the identification of aggregation modifiers," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    2. Ladan Khodaparast & Laleh Khodaparast & Guiqin Wu & Emiel Michiels & Rodrigo Gallardo & Bert Houben & Teresa Garcia & Matthias Vleeschouwer & Meine Ramakers & Hannah Wilkinson & Ramon Duran-Romaña & J, 2023. "Exploiting the aggregation propensity of beta-lactamases to design inhibitors that induce enzyme misfolding," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

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