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A globular protein exhibits rare phase behavior and forms chemically regulated orthogonal condensates in cells

Author

Listed:
  • Jinglei Nie

    (Westlake University
    Westlake University)

  • Xinyi Zhang

    (Westlake University
    Hamburg University of Technology)

  • Zhijuan Hu

    (Westlake University
    Westlake University
    Westlake University)

  • Wei Wang

    (Hamburg University of Technology)

  • Martin A. Schroer

    (University of Duisburg-Essen
    Hamburg Outstation c/o DESY)

  • Jie Ren

    (Chinese Academy of Agricultural Sciences)

  • Dmitri Svergun

    (Hamburg Outstation c/o DESY
    BIOSAXS GmbH)

  • Anyang Chen

    (Westlake University)

  • Peiguo Yang

    (Westlake University
    Westlake University)

  • An-Ping Zeng

    (Westlake University
    Westlake University
    Hamburg University of Technology
    Westlake University)

Abstract

Proteins with chemically regulatable phase separation are of great interest in the fields of biomolecular condensates and synthetic biology. Intrinsically disordered proteins (IDPs) are the dominating building blocks of biomolecular condensates which often lack orthogonality and small-molecule regulation desired to create synthetic biomolecular condensates or membraneless organelles (MLOs). Here, we discover a well-folded globular protein, lipoate-protein ligase A (LplA) from E. coli involved in lipoylation of enzymes essential for one-carbon and energy metabolisms, that exhibits structural homomeric oligomerization and a rare LCST-type reversible phase separation in vitro. In both E. coli and human U2OS cells, LplA can form orthogonal condensates, which can be specifically dissolved by its natural substrate, the small molecule lipoic acid and its analogue lipoamide. The study of LplA phase behavior and its regulatability expands our understanding and toolkit of small-molecule regulatable protein phase behavior with impacts on biomedicine and synthetic biology.

Suggested Citation

  • Jinglei Nie & Xinyi Zhang & Zhijuan Hu & Wei Wang & Martin A. Schroer & Jie Ren & Dmitri Svergun & Anyang Chen & Peiguo Yang & An-Ping Zeng, 2025. "A globular protein exhibits rare phase behavior and forms chemically regulated orthogonal condensates in cells," Nature Communications, Nature, vol. 16(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-57886-4
    DOI: 10.1038/s41467-025-57886-4
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    References listed on IDEAS

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