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

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  • Hopen K. Yang

    (University of Delaware)

  • Pragati K. Muthukumar

    (University of Delaware)

  • Wilfred Chen

    (University of Delaware)

Abstract

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.

Suggested Citation

  • Hopen K. Yang & Pragati K. Muthukumar & Wilfred Chen, 2025. "Synthetic protein degradation circuits using programmable cleavage and ligation by Sortase A," Nature Communications, Nature, vol. 16(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-63819-y
    DOI: 10.1038/s41467-025-63819-y
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    References listed on IDEAS

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    1. Alice Fletcher & Dean Clift & Emma Vries & Sergio Martinez Cuesta & Timothy Malcolm & Francesco Meghini & Raghothama Chaerkady & Junmin Wang & Abby Chiang & Shao Huan Samuel Weng & Jonathan Tart & Edm, 2023. "A TRIM21-based bioPROTAC highlights the therapeutic benefit of HuR degradation," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    2. Benjamin D. Towbin & Yael Korem & Anat Bren & Shany Doron & Rotem Sorek & Uri Alon, 2017. "Optimality and sub-optimality in a bacterial growth law," Nature Communications, Nature, vol. 8(1), pages 1-8, April.
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