Protein Structure and Folding
Structural Basis for Acetylated Histone H4 Recognition by the Human BRD2 Bromodomain*

https://doi.org/10.1074/jbc.M109.062422Get rights and content
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Recognition of acetylated chromatin by the bromodomains and extra-terminal domain (BET) family proteins is a hallmark for transcriptional activation and anchoring viral genomes to mitotic chromosomes of the host. One of the BET family proteins BRD2 interacts with acetylated chromatin during mitosis and leads to transcriptional activation in culture cells. Here, we report the crystal structures of the N-terminal bromodomain of human BRD2 (BRD2-BD1; residues 74–194) in complex with each of three different Lys-12-acetylated H4 peptides. The BRD2-BD1 recognizes the H4 tail acetylated at Lys-12 (H4K12ac), whereas the side chain of hypoacetylated Lys-8 of H4 binds at the cavity of the dimer interface of BRD2-BD1. From binding studies, we identified the BRD2-BD1 residues that are responsible for recognition of the Lys-12-acetylated H4 tail. In addition, mutation to Lys-8 in the Lys-12-acetylated H4 tail decreased the binding to BRD2-BD1, implicating the critical role of Lys-8 in the Lys-12-acetylated H4 tail for the recognition by BRD2-BD1. Our findings provide a structural basis for deciphering the histone code by the BET bromodomain through the binding with a long segment of the histone H4 tail, which presumably prevents erasure of the histone code during the cell cycle.

Chromatin/Regulation
Methods/X-ray Crystallography
Protein/Structure
Crystal Structure
Protein Domains
Acetylation
BET Family
BRD2 BD1
Bromodomain

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The atomic coordinates and structure factors (codes 2DVQ, 2DVR, and 2DVS) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

*

This work was authored, in whole or in part, by National Institutes of Health staff. This work was supported in part by the Program for Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation, by the RIKEN Structural Genomics/Proteomics Initiative, and the National Project on Protein Structural and Functional Analyses, Ministry of Education, Culture, Sports, Science and Technology of Japan.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1–6.

1

Both authors contributed equally to this work.

2

Present address: Laboratory of Viral Diseases, NIAID, National Institutes of Health Institutes of Health, Bethesda, MD 20892.

3

Present address: Dept. of Medical Genome Sciences, Graduate School of Frontier Sciences, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.