title: Crystal structure of the human BRD2 bromodomain: insights into dimerization and recognition of acetylated histone H4.
abstract: 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.
authors.affiliation: RIKEN Genomic Sciences Center, 1-7-22 Suehiro-cho, Tsurumi, Yokohama 230-0045, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Takashi
authors.initials: T
authors.lastname: Umehara
authors.forename: Kazumi
authors.initials: K
authors.lastname: Nakano
authors.forename: Moon Kyoo
authors.initials: MK
authors.lastname: Jang
authors.forename: Mikako
authors.initials: M
authors.lastname: Shirouzu
authors.forename: Satoshi
authors.initials: S
authors.lastname: Morita
authors.forename: Hiroko
authors.initials: H
authors.lastname: Uda-Tochio
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Hamana
authors.forename: Takaho
authors.initials: T
authors.lastname: Terada
authors.forename: Naruhiko
authors.initials: N
authors.lastname: Adachi
authors.forename: Takehisa
authors.initials: T
authors.lastname: Matsumoto
authors.forename: Akiko
authors.initials: A
authors.lastname: Tanaka
authors.forename: Masami
authors.initials: M
authors.lastname: Horikoshi
authors.forename: Keiko
authors.initials: K
authors.lastname: Ozato
authors.forename: Balasundaram
authors.initials: B
authors.lastname: Padmanabhan
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Yokoyama
mesh_terms: D000107:Acetylation; D000595:Amino Acid Sequence; D001665:Binding Sites; D018360:Crystallography, X-Ray; D019281:Dimerization; D006367:HeLa Cells; D006657:Histones / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000031:analogs & derivatives / Q000378:metabolism; D008969:Molecular Sequence Data; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry* / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D055672:Static Electricity; D014157:Transcription Factors; D000092468:Bromodomain Containing Proteins
chemical_list: D006657:Histones; D008239:Lysine; D017346:Protein Serine-Threonine Kinases; D014157:Transcription Factors; C098415:BRD2 protein, human; D000092468:Bromodomain Containing Proteins; C002315:N(alpha)-acetyllysine