De novo designed protein guiding targeted protein degradation
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 s...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-07-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-62050-z |
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| author | Zhendong Li Gan Qiao Xianghe Wang Ming Wang Jinyu Cheng Guipeng Hu Xiaomin Li Jing Wu Jia Liu Cong Gao Liming Liu |
| author_facet | Zhendong Li Gan Qiao Xianghe Wang Ming Wang Jinyu Cheng Guipeng Hu Xiaomin Li Jing Wu Jia Liu Cong Gao Liming Liu |
| author_sort | Zhendong Li |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-968a41c717574119b49f9ab182ca5ccb |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-968a41c717574119b49f9ab182ca5ccb2025-08-20T04:03:03ZengNature PortfolioNature Communications2041-17232025-07-0116111810.1038/s41467-025-62050-zDe novo designed protein guiding targeted protein degradationZhendong Li0Gan Qiao1Xianghe Wang2Ming Wang3Jinyu Cheng4Guipeng Hu5Xiaomin Li6Jing Wu7Jia Liu8Cong Gao9Liming Liu10School of Biotechnology and Key Laboratory of Industrial Biotechnology of Ministry of Education, Jiangnan UniversityDepartment of Pharmacology, School of Pharmacy, Southwest Medical UniversitySchool of Biotechnology and Key Laboratory of Industrial Biotechnology of Ministry of Education, Jiangnan UniversitySchool of Biotechnology and Key Laboratory of Industrial Biotechnology of Ministry of Education, Jiangnan UniversitySchool of Biotechnology and Key Laboratory of Industrial Biotechnology of Ministry of Education, Jiangnan UniversitySchool of Life Sciences and Health Engineering, Jiangnan UniversitySchool of Biotechnology and Key Laboratory of Industrial Biotechnology of Ministry of Education, Jiangnan UniversitySchool of Life Sciences and Health Engineering, Jiangnan UniversitySchool of Biotechnology and Key Laboratory of Industrial Biotechnology of Ministry of Education, Jiangnan UniversitySchool of Biotechnology and Key Laboratory of Industrial Biotechnology of Ministry of Education, Jiangnan UniversitySchool of Biotechnology and Key Laboratory of Industrial Biotechnology of Ministry of Education, Jiangnan UniversityAbstract 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.https://doi.org/10.1038/s41467-025-62050-z |
| spellingShingle | Zhendong Li Gan Qiao Xianghe Wang Ming Wang Jinyu Cheng Guipeng Hu Xiaomin Li Jing Wu Jia Liu Cong Gao Liming Liu De novo designed protein guiding targeted protein degradation Nature Communications |
| title | De novo designed protein guiding targeted protein degradation |
| title_full | De novo designed protein guiding targeted protein degradation |
| title_fullStr | De novo designed protein guiding targeted protein degradation |
| title_full_unstemmed | De novo designed protein guiding targeted protein degradation |
| title_short | De novo designed protein guiding targeted protein degradation |
| title_sort | de novo designed protein guiding targeted protein degradation |
| url | https://doi.org/10.1038/s41467-025-62050-z |
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