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<p>New, universal tools for targeted protein degradation in bacteria can help to accelerate protein function studies and antimicrobial research. We describe a new method for degrading bacterial proteins using plasmid-encoded degrader peptides which deliver target proteins for degradation by a highly conserved ClpXP protease. We demonstrate the mode of action of the degraders on a challenging essential target, GroEL. The studies in bacteria are complemented by in vitro binding and structural studies. Expression of degrader peptides results in a temperature-dependent growth inhibition and depletion of GroEL levels over time. The reduction of GroEL levels is accompanied by dramatic proteome alterations. The presented method offers a new alternative approach for regulating protein levels in bacteria without genomic modifications or tag fusions. Our studies demonstrate that ClpXP is an attractive protease for the future use in bacterial-targeted protein degradation.</p>

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Targeted protein degradation in Escherichia coli using CLIPPERs

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年6月25日

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  • Matylda Anna Izert-Nowakowska,
  • Maria Magdalena Klimecka,
  • Anna Antosiewicz,
  • Karol Wróblewski,
  • Jakub Józef Kowalski,
  • Katarzyna Justyna Bandyra,
  • Tomasz Góral,
  • Sebastian Kmiecik,
  • Remigiusz Adam Serwa,
  • Maria Wiktoria Górna

摘要

New, universal tools for targeted protein degradation in bacteria can help to accelerate protein function studies and antimicrobial research. We describe a new method for degrading bacterial proteins using plasmid-encoded degrader peptides which deliver target proteins for degradation by a highly conserved ClpXP protease. We demonstrate the mode of action of the degraders on a challenging essential target, GroEL. The studies in bacteria are complemented by in vitro binding and structural studies. Expression of degrader peptides results in a temperature-dependent growth inhibition and depletion of GroEL levels over time. The reduction of GroEL levels is accompanied by dramatic proteome alterations. The presented method offers a new alternative approach for regulating protein levels in bacteria without genomic modifications or tag fusions. Our studies demonstrate that ClpXP is an attractive protease for the future use in bacterial-targeted protein degradation.