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J. Biol. Chem., Vol. 282, Issue 6, 4193-4201, February 9, 2007

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Crystal Structure of the Human BRD2 Bromodomain

INSIGHTS INTO DIMERIZATION AND RECOGNITION OF ACETYLATED HISTONE H4^*

Yoshihiro Nakamura¹, Takashi Umehara¹, Kazumi Nakano, Moon Kyoo Jang, Mikako Shirouzu, Satoshi Morita, Hiroko Uda-Tochio, Hiroaki Hamana, Takaho Terada, Naruhiko Adachi^¶||, Takehisa Matsumoto, Akiko Tanaka, Masami Horikoshi^¶||, Keiko Ozato, Balasundaram Padmanabhan², and Shigeyuki Yokoyama^**3

From the RIKEN Genomic Sciences Center, 1-7-22 Suehiro-cho, Tsurumi, Yokohama 230-0045, Japan, the ^¶Horikoshi Gene Selector Project, Exploratory Research for Advanced Technology, Japan Science and Technology Corporation, 5-9-6 Tokodai, Tsukuba, Ibaraki 300-2635, Japan, the ^||Laboratory of Developmental Biology, Institute of Molecular and Cellular Biosciences, University of Tokyo, 1-1-1 Yayoi-cho, Bunkyo-ku, Tokyo 113-0032, Japan, the ^**Department of Biophysics and Biochemistry, Graduate School of Science, University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan, and the Laboratory of Molecular Growth Regulation, NICHD, National Institutes of Health, Bethesda, Maryland 20892

The BET (bromodomains and extra terminal domain) family proteins recognize acetylated chromatin through their bromodomain and act as transcriptional activators. One of the BET proteins, BRD2, associates with the transcription factor E2F, the mediator components CDK8 and TRAP220, and RNA polymerase II, as well as with acetylated chromatin during mitosis. BRD2 contains two bromodomains (BD1 and BD2), which are considered to be responsible for binding to acetylated chromatin. The BRD2 protein specifically recognizes the histone H4 tail acetylated at Lys¹². Here, we report the crystal structure of the N-terminal bromodomain (BD1, residues 74-194) of human BRD2. Strikingly, the BRD2 BD1 protein forms an intact dimer in the crystal. This is the first observation of a homodimer among the known bromodomain structures, through the buried hydrophobic core region at the interface. Biochemical studies also demonstrated BRD2 BD1 dimer formation in solution. The two acetyllysine-binding pockets and a negatively charged secondary binding pocket, produced at the dimer interface in BRD2 BD1, may be the unique features that allow BRD2 BD1 to selectively bind to the acetylated H4 tail.

Received for publication, June 22, 2006 , and in revised form, November 30, 2006.

The atomic coordinates and structure factors (code 1X0J) 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 supported in part by the RIKEN Structural Genomics/Proteomics Initiative; the National Project on Protein Structural and Functional Analyses; the Ministry of Education, Culture, Sports, Science, and Technology of Japan; and Exploratory Research for Advanced Technology Program grants from Japan Science and Technology Corp. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1-3.

¹ Both authors contributed equally to this work.

² To whom correspondence may be addressed. Tel.: 81-45-503-9474; Fax: 81-45-503-9473; E-mail: paddy{at}gsc.riken.jp.

³ To whom correspondence may be addressed. Tel.: 81-45-503-9197; Fax: 81-45-503-9195; E-mail: yokoyama{at}biochem.s.u-tokyo.ac.jp.

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