Key Takeaways & Executive Findings
- •• Over 30 types of lysine PTMs have been characterized, with about 300,000 modification sites identified, highlighting their extensive regulatory roles. • Mass spectrometry combined with antibody-based enrichment has been pivotal in advancing the global characterization of lysine PTMs. • Crosstalk between different lysine PTMs on histones and non-histone proteins adds complexity to gene regulation and disease mechanisms. • Targeting lysine PTM regulatory enzymes (writers, erasers, readers) presents a promising therapeutic strategy for various diseases.
Abstract
Lysine post-translational modifications (PTMs) are widespread and versatile protein PTMs that are involved in diverse biological processes by regulating the fundamental functions of histone and non-histone proteins. Dysregulation of lysine PTMs is implicated in many diseases, and targeting lysine PTM regulatory factors, including writers, erasers, and readers, has become an effective strategy for disease therapy. The continuing development of mass spectrometry (MS) technologies coupled with antibody-based affinity enrichment technologies greatly promotes the discovery and decoding of PTMs. The global characterization of lysine PTMs is crucial for deciphering the regulatory networks, molecular functions, and mechanisms of action of lysine PTMs. In this review, we focus on lysine PTMs, and provide a summary of the regulatory enzymes of diverse lysine PTMs and the proteomics advances in lysine PTMs by MS technologies. We also discuss the types and biological functions of lysine PTM crosstalks on histone and non-histone proteins and current druggable targets of lysine PTM regulatory factors for disease therapy.
1. Introduction
Protein post-translational modifications (PTMs) of the epsilon amine group at lysine residues, also known as lysine PTMs, are widespread and versatile protein PTMs that play crucial roles in diverse biological processes, including transcription regulation, signaling transduction, protein degradation, and cell metabolism [1–3]. Lysine PTMs greatly expand the biological functions of histone and non-histone proteins, and dysregulation of lysine PTMs is implicated in various diseases, such as cancer and metabolic diseases [4,5]. Targeting lysine PTM regulatory factors, including writers, erasers, and readers, has been demonstrated to be an effective therapeutic strategy for various diseases [6–11].
The global characterization of lysine PTMs is crucial for understanding their biological functions and regulatory mechanisms in different physiological and pathological states. The continuing development of mass spectrometry (MS) technologies coupled with antibody-based affinity enrichment technologies has greatly promoted the discovery and decoding of PTMs [12,13]. Currently, over 30 types of lysine PTMs have been characterized, and about 300,000 lysine PTM sites have been identified [14]. Accordingly, by system-wide characterization of lysine PTMs on histone and non-histone proteins, the regulatory networks, molecular functions, mechanisms of action, and druggable targets of lysine PTMs have been increasingly deciphered. We recently summarized the proteomics-based characterization of PTMs in drug discovery [15].
In this review, we focus on lysine PTMs, and provide a comprehensive summary of the regulatory enzymes of diverse lysine PTMs and the proteomics advances in lysine PTMs based on MS technologies. We discuss the types and biological functions of crosstalks between lysine PTMs on both histone and non-histone proteins, as well as the current druggable targets of lysine PTM regulatory factors for disease therapy.
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Bingbing Hao, Kaifeng Chen, Linhui Zhai, Muyin Liu, Bin Liu, Minjia Tan (2026). Substrate and Functional Diversity of Protein Lysine Post-translational Modifications. Genomics, Proteomics & Bioinformatics. https://doi.org/10.1093/gpbjnl/qzae019
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Frequently Asked Questions
What are lysine post-translational modifications (PTMs)?
Lysine PTMs are chemical modifications on the epsilon amine group of lysine residues in proteins, including methylation, acetylation, and ubiquitination, which regulate protein function and are involved in various biological processes.
How are lysine PTMs identified and characterized?
Lysine PTMs are identified using mass spectrometry (MS) technologies combined with antibody-based affinity enrichment, allowing for the global detection and quantification of modification sites.
What is the significance of PTM crosstalk?
PTM crosstalk refers to the interplay between different modifications on the same or different residues, which can synergistically or antagonistically regulate protein function, adding complexity to cellular signaling and gene regulation.
How can lysine PTMs be targeted for disease therapy?
By targeting the enzymes that write, erase, or read lysine PTMs (writers, erasers, readers), it is possible to modulate PTM levels and downstream effects, offering therapeutic strategies for diseases like cancer and metabolic disorders.
What are the main types of lysine PTMs discussed in this review?
The review discusses various lysine PTMs, including methylation, acetylation, and other acylations, and their regulatory enzymes, with a focus on their roles in histone and non-histone proteins.
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