The Chemical Biology of Reversible Lysine Post-translational Modifications

Abstract

Lysine (Lys) residues in proteins undergo a wide range of reversible post-translational modifications (PTMs), which can regulate enzyme activities, chromatin structure, protein-protein interactions, protein stability, and cellular localization. Here we discuss the ''writers,'' ''erasers,'' and ''readers'' of some of the common protein Lys PTMs and summarize examples of their major biological impacts. We also review chemical biology approaches, from small-molecule probes to protein chemistry technologies, that have helped to delineate Lys PTM functions and show promise for a diverse set of biomedical applications. ll

DNAzymes for amine and peptide lysine acylation

“…25,26 One such reaction is lysine (Lys) acylation, where Lys acetylation is critical for histones and in other contexts, [27][28][29][30] and many longer-chain Lys acylation PTMs [31][32][33] such as malonylation, 34,35 succinylation, 34,36 and glutarylation 37,38 have been discovered yet are poorly understood. 39 As an alternative to approaches that include introduction of Lys analogues, [40][41][42][43] nonsense codon suppression, [44][45][46][47][48][49] bottom-up ligation-based assembly strategies, [50][51][52] or enzymatic methods that typically require creation of a non-native protein by insertion of a specific target sequence, [53][54][55][56][57][58] DNAzymes are promising for top-down introduction of Lys acylation PTMs onto intact native proteins, [59][60][61][62][63][64][65] but only if DNAzymes can be identified with the fundamental catalytic ability of Lys acylation.…”

Fluorogenic probes for detecting deacylase and demethylase activity towards post-translationally-modified lysine residues

“…2,3 However, the mechanisms and specicity proles of many of the lysine N-modication enzymes responsible for these type of PTMs remain unexplored in many cases. 4 Similarly, the effect of many of these lysine N-modication reactions on protein structure and function and their biological signicance still needs to be more fully explored. [4][5][6][7] The availability of simple analytical methods to detect enzyme catalyzed N-functionalization and/or N-deprotection reactions of lysine residues in proteins would be very useful to explore how these type of PTMs affect cellular processes.…”

“…4 Similarly, the effect of many of these lysine N-modication reactions on protein structure and function and their biological signicance still needs to be more fully explored. [4][5][6][7] The availability of simple analytical methods to detect enzyme catalyzed N-functionalization and/or N-deprotection reactions of lysine residues in proteins would be very useful to explore how these type of PTMs affect cellular processes. Previous studies have explored the activity of lysine N-modication enzymes using radioisotope, 8 high-performance liquid chromatography (HPLC), 8 mass spectrometry, 8,9 enzyme-coupled assays [8][9][10][11][12] and antibody-based methods.…”

“… 2,3 However, the mechanisms and specificity profiles of many of the lysine N-modification enzymes responsible for these type of PTMs remain unexplored in many cases. 4 Similarly, the effect of many of these lysine N-modification reactions on protein structure and function and their biological significance still needs to be more fully explored. 4–7 …”

Editorial of Special Issue “Protein Post-Translational Modifications in Signal Transduction and Diseases”

“…Indeed, the same residue may be subjected to different mutually exclusive PTMs. For instance, it could happen that the same lysine may undergo methylation, acetylation, ubiquitylation, or sumoylation, and each of these may determine a different biological outcome [ 17 , 18 ]. In addition, proteins are subjected to several PTMs, that, when nearby, can affect each other by changing either protein folding or chemical surface [ 19 ].…”