Abstract
The understanding of biomolecular recognition of posttranslationally modified histone proteins is centrally important to the histone code hypothesis. Despite extensive binding and structural studies on the readout of histones, the molecular language by which posttranslational modifications on histone proteins are read remains poorly understood. Here we report physical-organic chemistry studies on the recognition of the positively charged trimethyllysine by the electron-rich aromatic cage containing PHD3 finger of KDM5A. The aromatic character of two tryptophan residues that solely constitute the aromatic cage of KDM5A was fine-tuned by the incorporation of fluorine substituents. Our thermodynamic analyses reveal that the wild-type and fluorinated KDM5A PHD3 fingers associate equally well with trimethyllysine. This work demonstrates that the biomolecular recognition of trimethyllysine by fluorinated aromatic cages is associated with weaker cation–π interactions that are compensated by the energetically more favourable trimethyllysine-mediated release of high-energy water molecules that occupy the aromatic cage.
Highlights
The understanding of biomolecular recognition of posttranslationally modified histone proteins is centrally important to the histone code hypothesis
Fluorination of tryptophan residues was ideal due to (i) fluorine’s electronegativity that can be exploited to reduce the electron density of tryptophan’s indole rings, and (ii) the comparable size of fluorine and hydrogen, allowing for minimal structural perturbations of the protein. It is presently unclear how the fluorination of the aromatic cage affects the energetics of water molecules that occupy such cages, our physical-organic approach takes into consideration the role of water in the readout of trimethyllysine by the KDM5A PHD3 finger
A strategy in which the aromatic character of tryptophan residues is perturbed by the introduction of fluorine substituents, while keeping all other parameters of the KDM5A–H3K4me[3] system unaltered, eliminates the contribution from trimethyllysine desolvation in our comparative analyses
Summary
The understanding of biomolecular recognition of posttranslationally modified histone proteins is centrally important to the histone code hypothesis. Despite extensive binding and structural studies on the readout of histones, the molecular language by which posttranslational modifications on histone proteins are read remains poorly understood. Recent structural and functional studies have revealed that histones that possess unmethylated and methylated lysine residues can be recognized by a large number of reader domain proteins that differ in the composition of the lysine recognition site[12,13]. Bonding appear to be of central importance in the recognition of unmethylated lysines by interacting reader domains (e.g. ADD, BAH, PZP)[13]. Electrostatic interactions and H-bonding play important roles in the readout of the lower methylation states Kme and Kme[2] via a cavity-insertion binding mode (e.g. by 53BP1 tandem tudor domains, MBT domains, ankyrin repeats)[13]
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