Abstract
Gaining a fundamental insight into the biomolecular recognition of posttranslationally modified histones by epigenetic reader proteins is of crucial importance to understanding the regulation of the activity of human genes. Here, we seek to establish whether trimethylthialysine, a simple trimethyllysine analogue generated through cysteine alkylation, is a good trimethyllysine mimic for studies on molecular recognition by reader proteins. Histone peptides bearing trimethylthialysine and trimethyllysine were examined for binding with five human reader proteins employing a combination of thermodynamic analyses, molecular dynamics simulations and quantum chemical analyses. Collectively, our experimental and computational findings reveal that trimethylthialysine and trimethyllysine exhibit very similar binding characteristics for the association with human reader proteins, thereby justifying the use of trimethylthialysine for studies aimed at dissecting the origin of biomolecular recognition in epigenetic processes that play important roles in human health and disease.
Highlights
Biomolecular recognition of posttranslationally modified histone proteins is centrally important to regulation of the activity of human genes [1]
A cysteine residue was introduced at position 4 of the histone peptide, which was site- reacted with (2-bromoethyl)trimethylammonium bromide to form trimethylthialysine
We examined both peptides for association with five human reader proteins (KDM5APHD3, PDB: 2KGI; TAF3PHD, PDB: 2K17; BPTFPHD, PDB: 2F6J; SGF29TTD, PDB: 3ME9; KDM4ATTD, PDB: 2GFA) using isothermal titration calorimetry (ITC)
Summary
Biomolecular recognition of posttranslationally modified histone proteins is centrally important to regulation of the activity of human genes [1]. To lysine ε-amino group, leading to three different methylation states (i.e., monomethyllysine Kme, dimethyllysine Kme and trimethyllysine Kme, Figure 1A), which can be removed by histone lysine demethylases (KDMs) [4,5]. Methylated lysine residues play different roles in epigenetic processes, as these marks are recognized by structurally diverse classes of epigenetic reader proteins. To gain a better understanding of the exact role of lysine methylation in epigenetics, it is important to develop novel chemical tools for studying the molecular mechanisms that govern the molecular recognition of methylated lysines by reader proteins. An installation of chemically modified methylated lysine analogues into histone proteins [7] and histone peptides [8,9,10,11]
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