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
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 CSHL Cancer Center Program > Cancer Genetics and Genomics Program |
| Depositing User: | Matt Covey |
| Date: | May 2018 |
| Date Deposited: | 01 Jun 2018 19:25 |
| Last Modified: | 05 Nov 2020 16:59 |
| PMCID: | PMC5949996 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/36703 |
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