The BRD3 ET domain recognizes a short peptide motif through a mechanism that is conserved across chromatin remodelers and transcriptional regulators

J Biol Chem. 2018 May 11;293(19):7160-7175. doi: 10.1074/jbc.RA117.000678. Epub 2018 Mar 22.


Members of the bromodomain and extra-terminal domain (BET) family of proteins (bromodomain-containing (BRD) 2, 3, 4, and T) are widely expressed and highly conserved regulators of gene expression in eukaryotes. These proteins have been intimately linked to human disease, and more than a dozen clinical trials are currently underway to test BET-protein inhibitors as modulators of cancer. However, although it is clear that these proteins use their bromodomains to bind both histones and transcription factors bearing acetylated lysine residues, the molecular mechanisms by which BET family proteins regulate gene expression are not well defined. In particular, the functions of the other domains such as the ET domain have been less extensively studied. Here, we examine the properties of the ET domain of BRD3 as a protein/protein interaction module. Using a combination of pulldown and biophysical assays, we demonstrate that BRD3 binds to a range of chromatin-remodeling complexes, including the NuRD, BAF, and INO80 complexes, via a short linear "KIKL" motif in one of the complex subunits. NMR-based structural analysis revealed that, surprisingly, this mode of interaction is shared by the AF9 and ENL transcriptional coregulators that contain an acetyl-lysine-binding YEATS domain and regulate transcriptional elongation. This observation establishes a functional commonality between these two families of cancer-related transcriptional regulators. In summary, our data provide insight into the mechanisms by which BET family proteins might link chromatin acetylation to transcriptional outcomes and uncover an unexpected functional similarity between BET and YEATS family proteins.

Keywords: AF9; BET family proteins; acetylation; bromodomain; extraterminal domain; nuclear magnetic resonance (NMR); protein structure; protein/protein interaction; transcriptional coactivator.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATPases Associated with Diverse Cellular Activities
  • Acetylation
  • Amino Acid Motifs
  • Amino Acid Sequence
  • Biophysical Phenomena
  • Chromatin Assembly and Disassembly*
  • DNA Helicases / metabolism
  • DNA-Binding Proteins / metabolism
  • Gene Expression Regulation / physiology
  • Gene Regulatory Networks
  • HEK293 Cells
  • Humans
  • Mi-2 Nucleosome Remodeling and Deacetylase Complex / metabolism
  • Nuclear Proteins / metabolism
  • Peptides / chemistry*
  • Protein Binding
  • Protein Domains
  • RNA-Binding Proteins / chemistry
  • RNA-Binding Proteins / metabolism*
  • RNA-Binding Proteins / physiology
  • Sequence Homology, Amino Acid
  • Trans-Activators / chemistry
  • Trans-Activators / metabolism*
  • Transcription Factors


  • BANF1 protein, human
  • BRD3 protein, human
  • CHD4 protein, human
  • DNA-Binding Proteins
  • Nuclear Proteins
  • Peptides
  • RNA-Binding Proteins
  • Trans-Activators
  • Transcription Factors
  • Mi-2 Nucleosome Remodeling and Deacetylase Complex
  • ATPases Associated with Diverse Cellular Activities
  • DNA Helicases
  • INO80 protein, human

Associated data

  • PDB/2N4Q
  • PDB/6BGG
  • PDB/6BGH