Elucidation of binding preferences of YEATS domains to site-specific acetylated nucleosome core particles

Kikuchi, Masaki; Morita, Satoshi; Goto, Mie; Wakamori, Masatoshi; Katsura, Kazushige; Hanada, Kazuharu; Shirouzu, Mikako; Umehara, Takashi

doi:10.1016/j.jbc.2022.102164

Cited by 7 publications

(15 citation statements)

References 70 publications

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“…46 This study also highlighted the engagement of YEATS domain with a small region of the histone tail when YEATS interacts with an acetylated nucleosome core particle. [46][47][48] It has previously been shown that the exposure of histone tails in the context of the full nucleosome is limited by histone tail/DNA interactions. 17, 49,50 Our MD studies also support that only partial exposure of the histone tails may be required for their engagement with a YEATS domain, and that the increased L8 length of YEATS may not prevent the engagement of the insertion mutant to H3K9ac mark on histone tails.…”

Section: Discussionmentioning

confidence: 78%

“…15 Recent studies on the ENL analogue AF9 containing YEATS domain that were performed in the context of a full nucleosome showed an additive role of acetylation and the engagement of two YEATS molecules on the same histone tails. 46 This study also highlighted the engagement of YEATS domain with a small region of the histone tail when YEATS interacts with an acetylated nucleosome core particle. [46][47][48] It has previously been shown that the exposure of histone tails in the context of the full nucleosome is limited by histone tail/DNA interactions.…”

Section: Discussionmentioning

confidence: 78%

“…15 In addition, studies on the ENL analog AF9 YEATS domain showed an additive role of acetylation and the engagement of two YEATS domains on the same histone tail in the context of a full nucleosome. 52 This study also highlighted that YEATS domains engage primarily with histone tail consensus motifs when they interact with an acetylated nucleosome core particle. [52][53][54] Our MD studies also support that only partial exposure of the histone tails may be required for binding to full nucleosomes, as the consensus motif and the residues directly adjacent to it have the largest influence on binding thermodynamics.…”

Section: Discussionmentioning

confidence: 80%

“…52 This study also highlighted that YEATS domains engage primarily with histone tail consensus motifs when they interact with an acetylated nucleosome core particle. [52][53][54] Our MD studies also support that only partial exposure of the histone tails may be required for binding to full nucleosomes, as the consensus motif and the residues directly adjacent to it have the largest influence on binding thermodynamics. In vitro, engagement of residues non-adjacent to the consensus motif, along with increased L8 length dynamics, may have a reduced effect on peptide selectivity than observed here or in experiments with histone tail mimics, as those residues may be interacting with nucleosomal DNA.…”

Section: Discussionmentioning

confidence: 80%

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

Baweja

Wereszczynski

2022

Preprint

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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.

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Section: Discussionmentioning

confidence: 78%

Section: Discussionmentioning

confidence: 78%

Section: Discussionmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 80%

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

Baweja

Wereszczynski

2022

Preprint

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show abstract

“…15 In addition, studies on the ENL analog AF9 YEATS domain showed an additive role of acetylation and the engagement of two YEATS domains on the same histone tail in the context of a full nucleosome. 52 This study also highlighted that YEATS domains engage primarily with histone tail consensus motifs when they interact with an acetylated nucleosome core particle. 52−54 Our MD studies also support that only partial exposure of the histone tails may be required for binding to full nucleosomes, as the consensus motif and the residues directly adjacent to it have the largest influences on binding thermodynamics.…”

Section: Mutations and Peptide Binding Alter Loop Dynamicsmentioning

confidence: 99%

Conformational and Thermodynamic Differences Underlying Wild-Type and Mutant Eleven-Nineteen-Leukemia YEATS Domain Specificity for Epigenetic Marks

Baweja

Wereszczynski

2023

J. Chem. Inf. Model.

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Histone post-translational modifications (PTMs) are interpreted by multiple reader domains and proteins to regulate gene expression. The eleven-nineteen-leukemia (ENL) 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 ENL 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 selectivities of YEATS domains for various lysine acetylation marks, although different experiments have provided contrasting views on the abilities of the insertion and deletion mutants to discern specific PTMs. Here, we have performed multiple molecular dynamics simulations of wild-type and insertion and deletion mutant YEATS domains free from and in complex with two PTM peptides: one that is acetylated at K9 of H3 and the other that is acetylated at 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 effects 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 overinterpretation of results obtained from experiments on reader domain-histone peptide binding in isolation and not in the full-length nucleosome context.

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Therapeutic targeting of BET bromodomain and other epigenetic acetylrecognition domain–containing factors

Gold,

Shilatifard

2024

Current Opinion in Genetics & Development

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Elucidation of binding preferences of YEATS domains to site-specific acetylated nucleosome core particles

Cited by 7 publications

References 70 publications

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

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

Conformational and Thermodynamic Differences Underlying Wild-Type and Mutant Eleven-Nineteen-Leukemia YEATS Domain Specificity for Epigenetic Marks

Therapeutic targeting of BET bromodomain and other epigenetic acetylrecognition domain–containing factors

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