Progressive Phosphorylation Modulates the Self-Association of a Variably Modified Histone H3 Peptide.

George V Papamokos,Anastasia S Politou,Efthimios Kaxiras,George Tziatzos,Spyros Georgatos,Dimitrios G Papageorgiou

doi:10.3389/fmolb.2021.698182

Abstract

Protein phosphorylation is a key regulatory mechanism in eukaryotic cells. In the intrinsically disordered histone tails, phosphorylation is often a part of combinatorial post-translational modifications and an integral part of the “histone code” that regulates gene expression. Here, we study the association between two histone H3 tail peptides modified to different degrees, using fully atomistic molecular dynamics simulations. Assuming that the initial conformations are either α-helical or fully extended, we compare the propensity of the two peptides to associate with one another when both are unmodified, one modified and the other unmodified, or both modified. The simulations lead to the identification of distinct inter- and intramolecular interactions in the peptide dimer, highlighting a prominent role of a fine-tuned phosphorylation rheostat in peptide association. Progressive phosphorylation appears to modulate peptide charge, inducing strong and specific intermolecular interactions between the monomers, which do not result in the formation of amorphous or ordered aggregates, as documented by experimental evidence derived from Circular Dichroism and NMR spectroscopy. However, upon complete saturation of positive charges by phosphate groups, this effect is reversed: intramolecular interactions prevail and dimerization of zero-charge peptides is markedly reduced. These findings underscore the role of phosphorylation thresholds in the dynamics of intrinsically disordered proteins. Phosphorylation rheostats might account for the divergent effects of histone modifications on the modulation of chromatin structure.

Highlights

Post-translational modifications (PTMs) of core and linker histones, either on their flexible parts or globular domains, are believed to be a part of a complex regulatory mechanism (Andrews et al, 2016a)
Several intra- and intermolecular interactions between modifiable amino acids of the H3 peptides persisted during the Molecular Dynamics (MD) simulations
We studied the association between phosphorylated and variably modified histone H3 tail peptides based on a novel combinatorial pattern identified in vivo using fully atomistic molecular dynamics simulations

Summary

Introduction

Post-translational modifications (PTMs) of core and linker histones, either on their flexible parts or globular domains, are believed to be a part of a complex regulatory mechanism (Andrews et al, 2016a). The PTM machinery is currently understood on the basis of the “histone or epigenetic code” hypothesis (Strahl and Allis, 2000; Gardner et al, 2011; Soloway, 2016) As per this hypothesis, single histone modifications and their combinations alter the structure of chromatin and/or generate a Phosphorylation and Histone Association binding platform for effector proteins, enabling gene activation or silencing (Hake and Allis, 2006). Single histone modifications and their combinations alter the structure of chromatin and/or generate a Phosphorylation and Histone Association binding platform for effector proteins, enabling gene activation or silencing (Hake and Allis, 2006) This hypothesis, is not the only interpretation of PTM functionality (Lee et al, 2010). A survey of curated databases reporting experimentally verified PTMs across organisms reveals that phosphorylation is by far the most common PTM: more than one-third of all eukaryotic proteins undergo reversible phosphorylation (Khoury et al, 2011; Huang et al, 2016; Ullah et al, 2016)

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Conclusion