Computational design and genetic incorporation of lipidation mimics in living cells

Ding, Wenwen; Liu, Chao; Chen, Yulin; Gu, Jiayu; Fang, Chengzhu; Hu, Linzhen; Zhang, Long; Yuan, Ying; Feng, Xin‐Hua; Lin, Shixian

doi:10.1038/s41589-023-01400-8

Cited by 8 publications

(8 citation statements)

References 40 publications

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“…Chem. Biol.2023 This study developed the computational design and genetic incorporation of functional lipidation mimics for efficient membrane association and albumin binding. Manipulating cation-pi interactions with genetically encoded tryptophan derivativesZhaoH.LiuC.DingW.TangL.FangY.ChenY.HuL.YuanY.FangD.LinS. Zhao, H. Liu, C. Ding, W. Tang, L. Fang, Y. Chen, Y. Hu, L. Yuan, Y. Fang, D. Lin, S. 10.1021/jacs.1c12944J. Am.…”

Section: Key Referencesmentioning

confidence: 99%

“…Chem. Biol.2023 This study developed the computational design and genetic incorporation of functional lipidation mimics for efficient membrane association and albumin binding.…”

Section: Key Referencesmentioning

confidence: 99%

Section: Computer-aided Design and Genetic Incorporation Of Lipidatio...mentioning

confidence: 99%

“…(G) Cartoon procedure of a CT26 colon carcinoma murine model. (H) Neo-2/15-4OctyF exhibited more potent anticancer activity than Neo-2/15-F. Reproduced with permission from ref . Copyright 2023 Springer Nature.…”

Section: Computer-aided Design and Genetic Incorporation Of Lipidatio...mentioning

confidence: 99%

“…These lipidation mimics can fully recapitulate the biochemical properties of natural lipidation in membrane association for probing its biological functions on signaling proteins and in albumin binding for designing long-acting protein drugs. (2) We demonstrate that the binding affinity between histone methylations and their corresponding readers can be substantially increased with genetically encoded electron-rich Trp derivatives. These engineered affinity-enhanced readers can be applied to enrich, image, and profile the interactome of chromatin methylations.…”

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New Strategies for Probing the Biological Functions of Protein Post-translational Modifications in Mammalian Cells with Genetic Code Expansion

Ding,

Zhao,

Chen

et al. 2023

Acc. Chem. Res.

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Conspectus Protein post-translational modification (PTM) is a major mechanism for functional diversification of the human genome and plays a crucial role in almost every aspect of cellular processes, and the dysregulation of the protein PTM network has been associated with a variety of human diseases. Using high-resolution mass spectrometry, protein PTMs can be efficiently discovered and profiled under various biological and physiological conditions. However, it is often challenging to address the biological function of PTMs with biochemical and mutagenesis-based approaches. Specifically, this field lacks methods that allow gain-of-function studies of protein PTMs to understand their functional consequences in living cells. In this context, the genetic code expansion (GCE) strategy has made tremendous progress in the direct installation of PTMs and their analogs in the form of noncanonical amino acids (ncAAs) for gain-of-function investigations. In addition to studying the biological functions of known protein PTMs, the discovery of new protein PTMs is even more challenging due to the lack of chemical information for designing specific enrichment methods. Genetically encoded ncAAs in the proteome can be used as specific baits to enrich and subsequently identify new PTMs by mass spectrometry. In this Account, we discuss recent developments in the investigation of the biological functions of protein PTMs and the discovery of protein PTMs using new GCE strategies. First, we leveraged a chimeric design to construct several broadly orthogonal translation systems (OTSs). These broad OTSs can be engineered to efficiently incorporate different ncAAs in both E. coli and mammalian cells. With these broad OTSs, we accomplish the following: (1) We develop a computer-aided strategy for the design and genetic incorporation of length-tunable lipidation mimics. These lipidation mimics can fully recapitulate the biochemical properties of natural lipidation in membrane association for probing its biological functions on signaling proteins and in albumin binding for designing long-acting protein drugs. (2) We demonstrate that the binding affinity between histone methylations and their corresponding readers can be substantially increased with genetically encoded electron-rich Trp derivatives. These engineered affinity-enhanced readers can be applied to enrich, image, and profile the interactome of chromatin methylations. (3) We report the identification and verification of a novel type of protein PTM, aminoacylated lysine ubiquitination, using genetically encoded PTM ncAAs as chemical probes. This approach provides a general strategy for the identification of unknown PTMs by increasing the abundance of PTM bait probes.

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Section: Key Referencesmentioning

confidence: 99%

“…Chem. Biol.2023 This study developed the computational design and genetic incorporation of functional lipidation mimics for efficient membrane association and albumin binding.…”

Section: Key Referencesmentioning

confidence: 99%

Section: Computer-aided Design and Genetic Incorporation Of Lipidatio...mentioning

confidence: 99%

Section: Computer-aided Design and Genetic Incorporation Of Lipidatio...mentioning

confidence: 99%

mentioning

confidence: 99%

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New Strategies for Probing the Biological Functions of Protein Post-translational Modifications in Mammalian Cells with Genetic Code Expansion

Ding,

Zhao,

Chen

et al. 2023

Acc. Chem. Res.

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Noncanonical Amino Acid Incorporation in Animals and Animal Cells

Kim,

Cho

et al. 2024

Chem. Rev.

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Noncanonical amino acids (ncAAs) are synthetic building blocks that, when incorporated into proteins, confer novel functions and enable precise control over biological processes. These small yet powerful tools offer unprecedented opportunities to investigate and manipulate various complex life forms. In particular, ncAA incorporation technology has garnered significant attention in the study of animals and their constituent cells, which serve as invaluable model organisms for gaining insights into human physiology, genetics, and diseases. This review will provide a comprehensive discussion on the applications of ncAA incorporation technology in animals and animal cells, covering past achievements, current developments, and future perspectives. CONTENTS 4.1.3. Danio rerio 4.1.4.

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The Biosynthesis and Applications of Protein Lipidation

Ding,

Gu,

et al. 2024

Chem. Rev.

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Protein lipidation dramatically affects protein structure, localization, and trafficking via remodeling protein−membrane and protein−protein interactions through hydrophobic lipid moieties. Understanding the biosynthesis of lipidated proteins, whether natural ones or mimetics, is crucial for reconstructing, validating, and studying the molecular mechanisms and biological functions of protein lipidation. In this Perspective, we first provide an overview of the natural enzymatic biosynthetic pathways of protein lipidation in mammalian cells, focusing on the enzymatic machineries and their chemical linkages. We then discuss strategies to biosynthesize protein lipidation in mammalian cells by engineering modification machineries and substrates. Additionally, we explore site-specific protein lipidation biosynthesis in vitro via enzyme-mediated ligations and in vivo primarily through genetic code expansion strategies. We also discuss the use of small molecule tools to modulate the process of protein lipidation biosynthesis. Finally, we provide concluding remarks and discuss future directions for the biosynthesis and applications of protein lipidation.

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Computational design and genetic incorporation of lipidation mimics in living cells

Cited by 8 publications

References 40 publications

New Strategies for Probing the Biological Functions of Protein Post-translational Modifications in Mammalian Cells with Genetic Code Expansion

New Strategies for Probing the Biological Functions of Protein Post-translational Modifications in Mammalian Cells with Genetic Code Expansion

Noncanonical Amino Acid Incorporation in Animals and Animal Cells

The Biosynthesis and Applications of Protein Lipidation

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