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

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.

Integrative transcriptomic, proteomic, and phosphoproteomic analysis on the defense response to Magnaporthe oryzae reveals different expression patterns at the molecular level of durably resistant rice cultivar Mowanggu

“…Recent studies have demonstrated that besides the abundance of the synthesized proteins, posttranslational modification (PTM) of the stress-related signaling proteins is particularly important to dynamically regulate signaling in response to invasion patterns originating from the pathogen ( Liu et al., 2019 ). Protein phosphorylation is one of the most thoroughly studied PTM and has been estimated to affect about 30% of total protein in plants ( Papamokos et al., 2021 ). For example, OsCERK1 functions in blast disease resistance by interacting with OsRLCK185 and transducing pathogen-associated molecular patterns immune signals into phosphorylation events to activate the MAPK Cascade ( Wang C. et al., 2017 ).…”

The Activated AMPK/mTORC2 Signaling Pathway Associated with Oxidative Stress in Seminal Plasma Contributes to Idiopathic Asthenozoospermia

“…Previous studies have reported that seminal peptides appear to have a role in sperm motility and thereby fertility [ 42 , 43 ]. Protein conformational changes, including protein/peptide aggregation, are often triggered by protein phosphorylation [ 44 , 45 ]. Protein phosphorylation plays a pivotal role in regulating biological processes, such as signal transduction and metabolic regulation, by changing protein conformation, activity, and interaction [ 45 , 46 ].…”

An in silico study of how histone tail conformation affects the binding affinity of ING family proteins

“…Previous experimental studies have suggested that the PHD finger of ING proteins can recognize the histone H3 tail with varying affinities depending on the methylation status of the K4 ( Champagne & Kutateladze, 2009 ; Soliman & Riabowol, 2007 ; Peña et al, 2006 ) as well as unmodified or various modifications like acetylation and phosphorylation ( Li & Li, 2012 ; Musselman & Kutateladze, 2011 ; Papamokos et al, 2021 ). The binding site of the PHD finger grips the K4 of the histone H3 tail while the R2 is coordinated in a neighboring pocket.…”