Genetically encoding ε-N-methacryllysine into proteins in live cells

Tian-Yi Zhu, Shi-Yi Chen, Mengdi Zhang, Heyu Li, Ting Wu, Emmanuel Ajiboye, Jia Wen Wang, Bi-Kun Jin, Dan-Dan Liu, Xintong Zhou, He Huang, Xiaobo Wan, Ke Sun, Peilong Lu, Yaxin Fu, Ying Yuan, Hai Song, Anna A. Sablina, Chao Tong, Long Zhang (), Ming Wu (), Haifan Wu () and Bing Yang ()
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Tian-Yi Zhu: Zhejiang University
Shi-Yi Chen: Zhejiang University
Mengdi Zhang: Zhejiang University
Heyu Li: Zhejiang University
Ting Wu: Zhejiang University
Emmanuel Ajiboye: Wichita State University
Jia Wen Wang: Wichita State University
Bi-Kun Jin: Zhejiang University
Dan-Dan Liu: Zhejiang University
Xintong Zhou: Zhejiang University
He Huang: Computational Medicine Beijing Co. Ltd.
Xiaobo Wan: Computational Medicine Beijing Co. Ltd.
Ke Sun: Westlake University
Peilong Lu: Westlake University
Yaxin Fu: Capital Medical University
Ying Yuan: Zhejiang University School of Medicine
Hai Song: Zhejiang University
Anna A. Sablina: VIB
Chao Tong: Zhejiang University
Long Zhang: Zhejiang University
Ming Wu: Zhejiang University School of Medicine
Haifan Wu: Wichita State University
Bing Yang: Zhejiang University

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: Abstract Lysine acylation is a ubiquitous post-translational modification (PTM) that plays pivotal roles in various cellular processes, such as transcription, metabolism, protein localization and folding. Thousands of lysine acylation sites have been identified based on advances in antibody enrichment strategies, highly sensitive analysis by mass spectrometry (MS), and bioinformatics. However, only 27 lysine methacrylation (Kmea) sites have been identified exclusively in histone proteins. It is hard to separate, purify and differentiate the Kmea modification from its structural isomer lysine crotonylation (Kcr) using general biochemical approaches. Here, we identify Kmea sites on a non-histone protein, Cyclophillin A (CypA). To investigate the functions of Kmea in CypA, we develop a general genetic code expansion approach to incorporate a non-canonical amino acid (ncAA) ε-N-Methacryllysine (MeaK) into target proteins and identify interacting proteins of methacrylated CypA using affinity-purification MS. We find that Kmea at CypA site 125 regulates cellular redox homeostasis, and HDAC1 is the regulator of Kmea on CypA. Moreover, we discover that genetically encode Kmea can be further methylated to ε-N-methyl-ε-N-methacrylation (Kmemea) in live cells.

Date: 2025
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DOI: 10.1038/s41467-025-57969-2

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