Co‐Translational Deposition of N6‐Acetyl‐L‐Lysine in Nascent Proteins Contributes to the Acetylome in Mammalian Cells
Abstract N6‐acetyl‐L‐lysine residue is abundant in dietary protein but little is known about its potential influences on the diet‐consumers. Herein, it is reported that Lysyl‐tRNA synthetase (KARS) mediates co‐translational deposition of diet‐derived N6‐acetyl‐L‐lysine (AcK) in nascent proteins to c...
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Wiley
2025-01-01
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| Online Access: | https://doi.org/10.1002/advs.202403309 |
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| author | Dingyuan Guo Nan Li Xiaoyan Zhang Runxin Zhou Jie He Xiao‐Ping Ding Weixing Yu Fuqiang Tong Sibi Yin Yu Wang Xin Xu Long Wang Mingzhu Fan Shan Feng Ke Liu Ke Tang Zhuqing Ouyang Yusong R Guo Yugang Wang |
| author_facet | Dingyuan Guo Nan Li Xiaoyan Zhang Runxin Zhou Jie He Xiao‐Ping Ding Weixing Yu Fuqiang Tong Sibi Yin Yu Wang Xin Xu Long Wang Mingzhu Fan Shan Feng Ke Liu Ke Tang Zhuqing Ouyang Yusong R Guo Yugang Wang |
| author_sort | Dingyuan Guo |
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| description | Abstract N6‐acetyl‐L‐lysine residue is abundant in dietary protein but little is known about its potential influences on the diet‐consumers. Herein, it is reported that Lysyl‐tRNA synthetase (KARS) mediates co‐translational deposition of diet‐derived N6‐acetyl‐L‐lysine (AcK) in nascent proteins to contribute to the acetylome in cells. Acetylated dietary protein is a direct source of AcK that can widely and substantially regulate the acetylome in multiple organs of mice. By analyzing the mechanisms underlying AcK contributing to the acetylome in mammalian cells, it is found that KARS can utilize AcK as an alternative substrate to produce N6‐acetyl‐l‐lysyl‐tRNA. The crystal structure of KARS in complex with AcK at 2.26 Å resolution shows that AcK shares the same substrate‐binding pocket as L‐lysine, allowed by a sidechain flip of Tyr499. The generated N6‐acetyl‐L‐lysyl‐tRNA introduces AcK into growing nascent polypeptide and results in protein acetylation, including the regions buried inside folded proteins that are post‐translational modification (PTM)‐inaccessible and functionally important. This undocumented protein modification mechanism is inherently different from PTM and termed as co‐translational modification (coTM). It is expected to extend the repertoire of acetylome and improve the understanding of protein modification mechanisms in cells. |
| format | Article |
| id | doaj-art-9ffd174a11854d3d81c536ff2ce64db0 |
| institution | Kabale University |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-01-01 |
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| series | Advanced Science |
| spelling | doaj-art-9ffd174a11854d3d81c536ff2ce64db02025-01-29T09:50:19ZengWileyAdvanced Science2198-38442025-01-01124n/an/a10.1002/advs.202403309Co‐Translational Deposition of N6‐Acetyl‐L‐Lysine in Nascent Proteins Contributes to the Acetylome in Mammalian CellsDingyuan Guo0Nan Li1Xiaoyan Zhang2Runxin Zhou3Jie He4Xiao‐Ping Ding5Weixing Yu6Fuqiang Tong7Sibi Yin8Yu Wang9Xin Xu10Long Wang11Mingzhu Fan12Shan Feng13Ke Liu14Ke Tang15Zhuqing Ouyang16Yusong R Guo17Yugang Wang18Department of Biochemistry and Molecular Biology School of Basic Medicine Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases Huazhong University of Science and Technology Wuhan Hubei 430030 ChinaDepartment of Biochemistry and Molecular Biology School of Basic Medicine Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases Huazhong University of Science and Technology Wuhan Hubei 430030 ChinaDepartment of Pathogen Biology, School of Basic Medicine, Tongji Medical College Huazhong University of Science and Technology Wuhan Hubei 430030 ChinaDepartment of Biochemistry and Molecular Biology School of Basic Medicine Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases Huazhong University of Science and Technology Wuhan Hubei 430030 ChinaDepartment of Biochemistry and Molecular Biology School of Basic Medicine Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases Huazhong University of Science and Technology Wuhan Hubei 430030 ChinaHubei Institute for Drug Control Wuhan Hubei 430075 ChinaDepartment of Biochemistry and Molecular Biology School of Basic Medicine Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases Huazhong University of Science and Technology Wuhan Hubei 430030 ChinaDepartment of Biochemistry and Molecular Biology School of Basic Medicine Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases Huazhong University of Science and Technology Wuhan Hubei 430030 ChinaDepartment of Biochemistry and Molecular Biology School of Basic Medicine Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases Huazhong University of Science and Technology Wuhan Hubei 430030 ChinaDepartment of Biochemistry and Molecular Biology School of Basic Medicine Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases Huazhong University of Science and Technology Wuhan Hubei 430030 ChinaSchool of Chemistry and Chemical Engineering and Hubei Key Laboratory of Bioinorganic Chemistry and Materia Medica Huazhong University of Science and Technology Wuhan Hubei 430074 ChinaSchool of Chemistry and Chemical Engineering and Hubei Key Laboratory of Bioinorganic Chemistry and Materia Medica Huazhong University of Science and Technology Wuhan Hubei 430074 ChinaMass Spectrometry & Metabolomics Core Facility The Biomedical Research Core Facility Center for Research Equipment and Facilities Westlake University Hangzhou Zhejiang 310024 ChinaMass Spectrometry & Metabolomics Core Facility The Biomedical Research Core Facility Center for Research Equipment and Facilities Westlake University Hangzhou Zhejiang 310024 ChinaDepartment of Biostatistics School of Public Health Cheeloo College of Medicine Shandong University Jinan 250000 ChinaDepartment of Biochemistry and Molecular Biology School of Basic Medicine Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases Huazhong University of Science and Technology Wuhan Hubei 430030 ChinaDepartment of Pathogen Biology, School of Basic Medicine, Tongji Medical College Huazhong University of Science and Technology Wuhan Hubei 430030 ChinaDepartment of Biochemistry and Molecular Biology School of Basic Medicine Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases Huazhong University of Science and Technology Wuhan Hubei 430030 ChinaDepartment of Biochemistry and Molecular Biology School of Basic Medicine Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases Huazhong University of Science and Technology Wuhan Hubei 430030 ChinaAbstract N6‐acetyl‐L‐lysine residue is abundant in dietary protein but little is known about its potential influences on the diet‐consumers. Herein, it is reported that Lysyl‐tRNA synthetase (KARS) mediates co‐translational deposition of diet‐derived N6‐acetyl‐L‐lysine (AcK) in nascent proteins to contribute to the acetylome in cells. Acetylated dietary protein is a direct source of AcK that can widely and substantially regulate the acetylome in multiple organs of mice. By analyzing the mechanisms underlying AcK contributing to the acetylome in mammalian cells, it is found that KARS can utilize AcK as an alternative substrate to produce N6‐acetyl‐l‐lysyl‐tRNA. The crystal structure of KARS in complex with AcK at 2.26 Å resolution shows that AcK shares the same substrate‐binding pocket as L‐lysine, allowed by a sidechain flip of Tyr499. The generated N6‐acetyl‐L‐lysyl‐tRNA introduces AcK into growing nascent polypeptide and results in protein acetylation, including the regions buried inside folded proteins that are post‐translational modification (PTM)‐inaccessible and functionally important. This undocumented protein modification mechanism is inherently different from PTM and termed as co‐translational modification (coTM). It is expected to extend the repertoire of acetylome and improve the understanding of protein modification mechanisms in cells.https://doi.org/10.1002/advs.202403309co‐translational modificationKARSprotein acetylation |
| spellingShingle | Dingyuan Guo Nan Li Xiaoyan Zhang Runxin Zhou Jie He Xiao‐Ping Ding Weixing Yu Fuqiang Tong Sibi Yin Yu Wang Xin Xu Long Wang Mingzhu Fan Shan Feng Ke Liu Ke Tang Zhuqing Ouyang Yusong R Guo Yugang Wang Co‐Translational Deposition of N6‐Acetyl‐L‐Lysine in Nascent Proteins Contributes to the Acetylome in Mammalian Cells Advanced Science co‐translational modification KARS protein acetylation |
| title | Co‐Translational Deposition of N6‐Acetyl‐L‐Lysine in Nascent Proteins Contributes to the Acetylome in Mammalian Cells |
| title_full | Co‐Translational Deposition of N6‐Acetyl‐L‐Lysine in Nascent Proteins Contributes to the Acetylome in Mammalian Cells |
| title_fullStr | Co‐Translational Deposition of N6‐Acetyl‐L‐Lysine in Nascent Proteins Contributes to the Acetylome in Mammalian Cells |
| title_full_unstemmed | Co‐Translational Deposition of N6‐Acetyl‐L‐Lysine in Nascent Proteins Contributes to the Acetylome in Mammalian Cells |
| title_short | Co‐Translational Deposition of N6‐Acetyl‐L‐Lysine in Nascent Proteins Contributes to the Acetylome in Mammalian Cells |
| title_sort | co translational deposition of n6 acetyl l lysine in nascent proteins contributes to the acetylome in mammalian cells |
| topic | co‐translational modification KARS protein acetylation |
| url | https://doi.org/10.1002/advs.202403309 |
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