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<p>Engineering synthetic intrinsically disordered proteins (synIDPs) enables regulation of biomolecular condensation and protein solubility. However, limited understanding of how sequence-dependent interaction cooperativity relates to the fitness impacts of synIDPs on endogenous cellular processes constrains our design capability. Here, to circumvent this design challenge, we present a systematic directed evolution method for the evolution of synIDPs capable of mediating diverse phase behaviors in living cells. The selection methods allow us to evolve a toolbox of synIDPs with distinct phase behaviors and thermoresponsive features in living cells, leading to the evolution of synthetic condensates. The reverse-selection method further allows us to select synIDPs as solubility tags. We demonstrate the applications of the evolved synIDPs in protein circuits to (1) regulate intracellular protein activity and (2) reverse antibiotic resistance. Our systematic evolution and selection strategies provide a versatile platform for developing synIDPs for broad applications in synthetic biology and biotechnology.</p><p></p>

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Directed evolution of functional intrinsically disordered proteins

  • 期刊论文

  • 发表日期：

    2026年1月9日

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  • Yuefeng Ma,
  • Leshan Yang,
  • Yantong Chen,
  • Michael W. Chen,
  • Wen Yu,
  • Yifan Dai

摘要

Engineering synthetic intrinsically disordered proteins (synIDPs) enables regulation of biomolecular condensation and protein solubility. However, limited understanding of how sequence-dependent interaction cooperativity relates to the fitness impacts of synIDPs on endogenous cellular processes constrains our design capability. Here, to circumvent this design challenge, we present a systematic directed evolution method for the evolution of synIDPs capable of mediating diverse phase behaviors in living cells. The selection methods allow us to evolve a toolbox of synIDPs with distinct phase behaviors and thermoresponsive features in living cells, leading to the evolution of synthetic condensates. The reverse-selection method further allows us to select synIDPs as solubility tags. We demonstrate the applications of the evolved synIDPs in protein circuits to (1) regulate intracellular protein activity and (2) reverse antibiotic resistance. Our systematic evolution and selection strategies provide a versatile platform for developing synIDPs for broad applications in synthetic biology and biotechnology.