Structural Mechanism of Transcriptional Regulator NSD3 Recognition by the ET Domain of BRD4.
The bromodomains and extra-terminal domain (BET) proteins direct gene transcription in chromatin, and represent new drug targets for cancer and inflammation. Here we report that the ET domain of the BET protein BRD4 recognizes an amphipathic protein sequence motif through establishing a two-strand antiparallel β sheet anchored on a hydrophobic cleft of the three-helix bundle. This structural mechanism likely explains BRD4 interactions with numerous cellular and viral proteins such as Kaposi's sarcoma-associated herpesvirus latency-associated nuclear antigen, and NSD3 whose interaction with BRD4 via this ET domain mechanism is essential for acute myeloid leukemia maintenance.
Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The First Hospital and Institute of Epigenetic Medicine, Jilin University, Changchun, 130061, Jilin, China.
Qiang
Q
Zhang
Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The First Hospital and Institute of Epigenetic Medicine, Jilin University, Changchun, 130061, Jilin, China.
Lei
L
Zeng
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; Molecular and Cellular Biology Program, Stony Brook University, Stony Brook, NY 11794, USA.
Chen
C
Shen
The First Hospital and Institute of Epigenetic Medicine, Jilin University, Changchun, 130061, Jilin, China.
Ying
Y
Ju
Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Tsuyoshi
T
Konuma
The First Hospital and Institute of Epigenetic Medicine, Jilin University, Changchun, 130061, Jilin, China.
Chengcheng
C
Zhao
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
Christopher R
CR
Vakoc
Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: ming-ming.zhou@mssm.edu.
Ming-Ming
MM
Zhou
D001665:Binding Sites; D018797:Cell Cycle Proteins; D011495:Histone-Lysine N-Methyltransferase / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D062105:Molecular Docking Simulation; D009687:Nuclear Proteins / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D014157:Transcription Factors / Q000737:chemistry* / Q000378:metabolism; D000092468:Bromodomain Containing Proteins
D018797:Cell Cycle Proteins; D011495:Histone-Lysine N-Methyltransferase; D009687:Nuclear Proteins; D014157:Transcription Factors; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C432968:NSD3 protein, human