Conformational and Thermodynamic Differences Underlying Wild-type and Mutant ENL YEATS Domain Specificity for Epigenetic Marks

Abstract

Histone post-translational modifications (PTMs) are interpreted by multiple reader domains and proteins to regulate gene expression. The YEATS domain is a prototypical PTM reader that recognizes multiple lysine acetylation marks on the histone H3 tails as a way of recruiting chromatin remodellers. Two YEATS mutations have been identified which have been linked with leukemia, Wilms tumor, and other forms of cancer and result in either an insertion or deletion of residues in the loop connecting beta sheets distant from the protein active site. In vitro experiments have shown that these mutations modulate the selectivity of YEATS domains for various lysine acetylation marks, although different experiments have provided contrasting views on the ability of the insertion and deletion mutants to discern specific PTMs. Here, we have performed multiple molecular dynamics simulations of wild-type, insertion, and deletion mutant YEATS domains free from and in complex with two PTM mimicking peptides: one that mimics acetylation on residue K9 of H3 and the other that mimics acetylation on residue K27 of H3. Results show that these two peptides have distinct flexibilities and binding energetics when bound to YEATS domains, and that these properties are affected by interactions with residues within and outside of the peptide consensus motif. Furthermore, these properties are modulated by the YEATS insertion and deletion mutants, which results in disparate binding affects in these systems. Together, these results suggest that only the partial exposure of histone tails is sufficient in the context of nucleosomes for YEATS-mediated recognition of acetylation marks on histone tails. They also caution against the over-interpretation of results obtained from experiments on reader domain-histone peptide binding in isolation and not in the full-length nucleosome context.