De novo designed protein guiding targeted protein degradation

Zhendong Li, Gan Qiao, Xianghe Wang, Ming Wang, Jinyu Cheng, Guipeng Hu, Xiaomin Li, Jing Wu, Jia Liu, Cong Gao () and Liming Liu ()
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Zhendong Li: Jiangnan University
Gan Qiao: Southwest Medical University
Xianghe Wang: Jiangnan University
Ming Wang: Jiangnan University
Jinyu Cheng: Jiangnan University
Guipeng Hu: Jiangnan University
Xiaomin Li: Jiangnan University
Jing Wu: Jiangnan University
Jia Liu: Jiangnan University
Cong Gao: Jiangnan University
Liming Liu: Jiangnan University

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract Targeted protein degradation is a powerful tool for biological research, cell therapy, and synthetic biology. However, conventional methods often depend on pre-fused degrons or chemical degraders, limiting their wider applications. Here we develop a guided protein labeling and degradation system (GPlad) in Escherichia coli, using de novo designed guide proteins and arginine kinase (McsB) for precise degradation of various proteins, including fluorescent proteins, metabolic enzymes, and human proteins. We expand GPlad into versatile tools such as antiGPlad, OptoGPlad, and GPTAC, enabling reversible inhibition, optogenetic regulation, and biological chimerization. The combination of GPlad and antiGPlad allows for programmable circuit construction, including ON/OFF switches, signal amplifiers, and oscillators. OptoGPlad-mediated degradation of MutH accelerates E. coli evolution under protocatechuic acid stress, reducing the required generations from 220 to 100. GPTAC-mediated degradation of AroE enhanced the titer of 3-dehydroshikimic acid to 92.6 g/L, a 23.8% improvement over the conventional CRISPR interference method. We provide a tunable, plug-and-play strategy for straightforward protein degradation without the need for pre-fusion, with substantial implications for synthetic biology and metabolic engineering.

Date: 2025
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DOI: 10.1038/s41467-025-62050-z

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