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

Wai, D. C., Szyszka, T. N., Campbell, A. E., Kwong, C., Wilkinson-White, L. E., Silva, A. P. G., Low, J. K. K., Kwan, A. H., Gamsjaeger, R., Chalmers, J. N., Patrick, W. M., Lu, B., Vakoc, C. R., Blobel, G., Mackay, J. P. (May 2018) The BRD3 ET domain recognizes a short peptide motif through a mechanism that is conserved across chromatin remodelers and transcriptional regulators. J Biol Chem, 293 (19). pp. 7160-7175. ISSN 0021-9258

URL: https://www.ncbi.nlm.nih.gov/pubmed/29567837
DOI: 10.1074/jbc.RA117.000678

Abstract

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 therapies. 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 acetyllysine-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.

Item Type: Paper
Uncontrolled Keywords: Af9 BET-family proteins Bromodomain acetylation extraterminal domain nuclear magnetic resonance (NMR) protein structure protein-protein interaction transcriptional coactivator
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > transcription
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > BET bromodomain coactivator protein
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > chromatin remodeling
CSHL Authors:
Communities: CSHL labs > Vakoc lab
Depositing User: Matt Covey
Date: May 2018
Date Deposited: 01 Jun 2018 19:25
Last Modified: 01 Jun 2018 19:25
PMCID: PMC5949996
Related URLs:
URI: http://repository.cshl.edu/id/eprint/36703

Actions (login required)

Administrator's edit/view item Administrator's edit/view item
CSHL HomeAbout CSHLResearchEducationNews & FeaturesCampus & Public EventsCareersGiving