Abstract
Histone lysine acetylation and methylation have an important role during gene transcription in a chromatin context1,2. Knowledge concerning the types of protein modules that can interact with acetyl-lysine has so far been limited to bromodomains1. Recently, a tandem plant homeodomain (PHD) finger3 (PHD1–PHD2, or PHD12) of human DPF3b, which functions in association with the BAF chromatin remodelling complex to initiate gene transcription during heart and muscle development, was reported to bind histones H3 and H4 in an acetylation-sensitive manner4, making it the first alternative to bromodomains for acetyl-lysine binding5. Here we report the structural mechanism of acetylated histone binding by the double PHD fingers of DPF3b. Our three-dimensional solution structures and biochemical analysis of DPF3b highlight the molecular basis of the integrated tandem PHD finger, which acts as one functional unit in the sequence-specific recognition of lysine-14-acetylated histone H3 (H3K14ac). Whereas the interaction with H3 is promoted by acetylation at lysine 14, it is inhibited by methylation at lysine 4, and these opposing influences are important during transcriptional activation of the mouse DPF3b target genes Pitx2 and Jmjd1c. Binding of this tandem protein module to chromatin can thus be regulated by different histone modifications during the initiation of gene transcription.
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Accession codes
Primary accessions
Protein Data Bank
Data deposits
The structural coordinates of human DPF3b PHD12 in complex with H3K14ac, H3, H4-Nac, or H4K16ac peptides are deposited in the Protein Data Bank under accession codes 2kwj, 2kwk, 2kwn and 2kwo, respectively. Accession codes for the chemical shift assignments of the corresponding NMR structures deposited at the BioMagResBank are 16858, 16859, 16861 and 16865, respectively.
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Acknowledgements
We acknowledge the use of the NMR Facility at the New York Structural Biology Center. We thank S. Hearn of Cold Spring Harbor Laboratory microscopy facility for help with confocal microscopy study, and A. Buku and G. Gerona-Navarro for technical advice on peptide binding analysis. This work was supported by grants from the National Institutes of Health (M.-M.Z.).
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M.-M.Z. and M.J.W. designed the study; Q.Z. generated constructs and protein samples, and contributed to the immunofluorescence study; L.Z. determined the protein structures; A.N.P. contributed to the protein biochemistry study; L.Z. and Q.Z. performed protein and peptide binding study; S.L. and M.J.W. carried out the cell biology experiments; M.-M.Z. supervised the project; all authors contributed to manuscript preparation.
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Zeng, L., Zhang, Q., Li, S. et al. Mechanism and regulation of acetylated histone binding by the tandem PHD finger of DPF3b. Nature 466, 258–262 (2010). https://doi.org/10.1038/nature09139
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DOI: https://doi.org/10.1038/nature09139
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