Crystal structure of the human BRD2 bromodomain: insights into dimerization and recognition of acetylated histone H4.
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.
Nakamura
Yoshihiro
Y
RIKEN Genomic Sciences Center, 1-7-22 Suehiro-cho, Tsurumi, Yokohama 230-0045, Japan.
Umehara
Takashi
T
Nakano
Kazumi
K
Jang
Moon Kyoo
MK
Shirouzu
Mikako
M
Morita
Satoshi
S
Uda-Tochio
Hiroko
H
Hamana
Hiroaki
H
Terada
Takaho
T
Adachi
Naruhiko
N
Matsumoto
Takehisa
T
Tanaka
Akiko
A
Horikoshi
Masami
M
Ozato
Keiko
K
Padmanabhan
Balasundaram
B
Yokoyama
Shigeyuki
S
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
D006657:Histones; D008239:Lysine; D017346:Protein Serine-Threonine Kinases; D014157:Transcription Factors; C098415:BRD2 protein, human; D000092468:Bromodomain Containing Proteins; C002315:N(alpha)-acetyllysine