Work

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

Year: 2025

Type: article

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 temporal 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, new conditional degradation phenotypes can be readily adapted with minimal modifications to the design. This new 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 operationsdepending on the input combinations. The flexibility to temporally modulate the level of multiple native intracellular proteins can potentially lead to applications from therapy to diagnostics and biotechnology.

Source: Nature Communications

DOI: 10.1038/s41467-025-63819-y

Authors: Hopen K. Yang, Pragati K. Muthukumar, Wilfred Chen

Institution: University of Delaware

Language: English

Topic: Protein Degradation and Inhibitors

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

Open Access status: gold

Estimated APC paid: $6,990

Funders: National Science Foundation, National Institutes of Health, National Institute of General Medical Sciences, Division of Chemical, Bioengineering, Environmental, and Transport Systems