Dataset Information

Distinct mode of methylated lysine-4 of histone H3 recognition by tandem tudor-like domains of Spindlin1.

ABSTRACT: Recognition of methylated histone tail lysine residues by tudor domains plays important roles in epigenetic control of gene expression and DNA damage response. Previous studies revealed the binding of methyllysine in a cage of aromatic residues, but the molecular mechanism by which the sequence specificity for surrounding histone tail residues is achieved remains poorly understood. In the crystal structure of a trimethylated histone H3 lysine 4 (H3K4) peptide bound to the tudor-like domains of Spindlin1 presented here, an atypical mode of methyllysine recognition by an aromatic pocket of Spindlin1 is observed. Furthermore, the histone sequence is recognized in a distinct manner involving the amino terminus and a pair of arginine residues of histone H3, and disruption of the binding impaired stimulation of pre-RNA expression by Spindlin1. Our analysis demonstrates considerable diversities of methyllysine recognition and sequence-specific binding of histone tails by tudor domains, and the revelation furthers the understanding of tudor domain proteins in deciphering epigenetic marks on histone tails.

SUBMITTER: Yang N

PROVIDER: S-EPMC3497761 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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Distinct mode of methylated lysine-4 of histone H3 recognition by tandem tudor-like domains of Spindlin1.

Yang Na N Wang Weixiang W Wang Yan Y Wang Mingzhu M Zhao Qiang Q Rao Zihe Z Zhu Bing B Xu Rui-Ming RM

Proceedings of the National Academy of Sciences of the United States of America 20121017 44

Recognition of methylated histone tail lysine residues by tudor domains plays important roles in epigenetic control of gene expression and DNA damage response. Previous studies revealed the binding of methyllysine in a cage of aromatic residues, but the molecular mechanism by which the sequence specificity for surrounding histone tail residues is achieved remains poorly understood. In the crystal structure of a trimethylated histone H3 lysine 4 (H3K4) peptide bound to the tudor-like domains of S ...[more]

PMID: 23077255

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Project description:BackgroundHistone demethylase, JMJD2A, specifically recognizes and binds to methylated lysine residues at histone H3 and H4 tails (especially trimethylated H3K4 (H3K4me3), trimethylated H3K9 (H3K9me3) and di,trimethylated H4K20 (H4K20me2, H4K20me3)) via its tandem tudor domains. Crystal structures of JMJD2A-tudor binding to H3K4me3 and H4K20me3 peptides are available whereas the others are not. Complete picture of the recognition of the four histone peptides by the tandem tudor domains yet remains to be clarified.Methodology/principal findingsWe report a detailed molecular dynamics simulation and binding energy analysis of the recognition of JMJD2A-tudor with four different histone tails. 25 ns fully unrestrained molecular dynamics simulations are carried out for each of the bound and free structures. We investigate the important hydrogen bonds and electrostatic interactions between the tudor domains and the peptide molecules and identify the critical residues that stabilize the complexes. Our binding free energy calculations show that H4K20me2 and H3K9me3 peptides have the highest and lowest affinity to JMJD2A-tudor, respectively. We also show that H4K20me2 peptide adopts the same binding mode with H4K20me3 peptide, and H3K9me3 peptide adopts the same binding mode with H3K4me3 peptide. Decomposition of the enthalpic and the entropic contributions to the binding free energies indicate that the recognition of the histone peptides is mainly driven by favourable van der Waals interactions. Residue decomposition of the binding free energies with backbone and side chain contributions as well as their energetic constituents identify the hotspots in the binding interface of the structures.ConclusionEnergetic investigations of the four complexes suggest that many of the residues involved in the interactions are common. However, we found two receptor residues that were related to selective binding of the H3 and H4 ligands. Modifications or mutations on one of these residues can selectively alter the recognition of the H3 tails or the H4 tails.

Dataset Information

Distinct mode of methylated lysine-4 of histone H3 recognition by tandem tudor-like domains of Spindlin1.

Publications

Distinct mode of methylated lysine-4 of histone H3 recognition by tandem tudor-like domains of Spindlin1.

Similar Datasets

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