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<p>BioPROTACs are heterobifunctional proteins designed for targeted protein degradation (TPD). They are useful not only for probing protein functions but also offer a therapeutic avenue for modulating disease-related proteins. To extend the use of TPD beyond just protein attenuation, we introduce a synthetic framework for logic-gated, switchable TPD to achieve conditional control of protein content. By exploiting both the cleavage and ligation functionalities of Sortase A (SrtA), we present a new strategy utilizing SrtA as the control input to direct bioPROTAC activity for switchable TPD. Furthermore, by layering the SrtA input with protease gating, conditional degradation phenotypes can be readily adapted with minimal modifications to the design. This <Emphasis Type="BoldUnderline">L</Emphasis>ogic-gated <Emphasis Type="BoldUnderline">A</Emphasis>dPROM deploying <Emphasis Type="BoldUnderline">S</Emphasis>rtA-mediated <Emphasis Type="BoldUnderline">E</Emphasis>lement <Emphasis Type="BoldUnderline">R</Emphasis>ecombination (<Emphasis Type="BoldUnderline">LASER</Emphasis>) platform allows us to expand the possible protein degradation outcomes in mammalian cells using Boolean logic operations depending on the input combinations. The flexibility to modulate the level of multiple native intracellular proteins can potentially lead to applications from therapy to diagnostics and biotechnology.</p>

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Synthetic protein degradation circuits using programmable cleavage and ligation by Sortase A

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年9月30日

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  • Hopen K. Yang,
  • Pragati K. Muthukumar,
  • Wilfred Chen

摘要

BioPROTACs are heterobifunctional proteins designed for targeted protein degradation (TPD). They are useful not only for probing protein functions but also offer a therapeutic avenue for modulating disease-related proteins. To extend the use of TPD beyond just protein attenuation, we introduce a synthetic framework for logic-gated, switchable TPD to achieve conditional control of protein content. By exploiting both the cleavage and ligation functionalities of Sortase A (SrtA), we present a new strategy utilizing SrtA as the control input to direct bioPROTAC activity for switchable TPD. Furthermore, by layering the SrtA input with protease gating, conditional degradation phenotypes can be readily adapted with minimal modifications to the design. This Logic-gated AdPROM deploying SrtA-mediated Element Recombination (LASER) platform allows us to expand the possible protein degradation outcomes in mammalian cells using Boolean logic operations depending on the input combinations. The flexibility to modulate the level of multiple native intracellular proteins can potentially lead to applications from therapy to diagnostics and biotechnology.