Intrinsically disordered proteins (IDPs) and intrinsically disordered regions (IDRs) are proteins or parts of proteins that lack a defined three-dimensional structure. The discovery of IDPs and IDRs has disproven the theory that the three-dimensional structure of a protein defines its function. Proteins that are vital in many life-sustaining cellular processes often have IDRs, including transcription factors and proteins involved in the storage of genetic material. IDRs have often been found to be post-translationally modified to complete their function. There is no defined set of rules governing how post translational modifications (PTMs) affect the conformational ensembles of IDRs, therefore changes must be experimentally determined for each protein. IDRs are found in vital proteins involved in the storage of genetic material, called histone proteins. DNA wraps around histone proteins, which contain intrinsically disordered tails, to keep itself compact. To access DNA that is wrapped around histones, the DNA must be loosened. It has been theorized that lysine acetylation of the histone tails results in loosening of the DNA to become available for transcription. It is not known how the conformational ensemble of the histone 4 (H4) tail changes upon acetylation of lysine residues, or how DNA compaction is affected. Nuclear Magnetic Resonance (NMR) spectroscopy was utilized to observe chemical shift perturbations upon lysine acetylation, from which small changes in peptide secondary structure can be determined. Chemical shift perturbation data can be compared between acetylated and unacetylated H4 tail to demonstrate changes to its chemical environment upon acetylation. Three-dimensional NMR data for acetylated and unacetylated H4 tail can be compared against thousands of NMR spectra for proteins with known secondary structure to determine secondary structure propensity for individual residues of the H4 tail.  Circular dichroism (CD), size exclusion chromatography with multi-angle light scattering (SEC-MALS) and small angle X-ray scattering (SAXS) can be used in conjunction with NMR to provide complementary information to chemical shift perturbations. Determination of structural ensemble changes to the H4 tail upon acetylation allows for better understanding of the mechanism of DNA compaction. In addition, this understanding allows for these methods to be applied to other proteins that contain IDRs that also play important roles within protein synthesis.

NMR analysis of acetylation-induced structural ensemble changes to histone (H4) tail

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