Histone Recognition and Large-Scale Structural Analysis of the Human Bromodomain Family

By P. Filippakopoulos, S. Picaud, M. Mangos, T. Keates, Jean-Philippe Lambert, Dalia Barsyte-Lovejoy, I. Felletár, R. Volkmer, S. Müller, Tony Pawson and 3 more. Cell, 2012

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Summary Bromodomains (BRDs) are protein interaction modules that specifically recognize ε-N-lysine acetylation motifs, a key event in the reading process of epigenetic marks. The 61 BRDs in the human genome cluster into eight families based on structure/sequence similarity. Here, we present 29 high-resolution crystal structures, covering all BRD families. Comprehensive crossfamily structural analysis identifies conserved and family-specific structural features that are necessary for specific acetylation-dependent substrate recognition. Screening of more than 30 representative BRDs against systematic histone-peptide arrays identifies new BRD substrates and reveals a strong influence of flanking posttranslational modifications, such as acetylation and phosphorylation, suggesting that BRDs recognize combinations of marks rather than singly acetylated sequences. We further uncovered a structural mechanism for the simultaneous binding and recognition of diverse diacetyl-containing peptides by BRD4. These data provide a foundation for structure-based drug design of specific inhibitors for this emerging target family.

Subfields: Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/8708269d8cf3bf58ebd02891c138bd5595422870

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Citations in the corpus

Modification of enhancer chromatin: what, how and why? (2013, background): “…associate with nucleosomal DNA, preceding and commonly also enabling occupancy of other TFs via repositioning nucleosomes, recruiting chromatin modifiers, or protecting enhancer regions from DNA methylation (Ghisletti et al., 2010; Sérandour et al., 2011; Zaret and Carroll, 2011) (Figure 2B).”
Plasticity in binding confers selectivity in ligand induced protein degradation (2018, neutral): “CRBN binds the BRD4 BD1 α C helix (aa 145 – 161) and residues in the BRD4 BD1 ZA loop (aa 76 – 104) 31 .”
Interpreting thelanguage of histone and DNA modifications (2014, background): “This result paved the way for subsequent characterization of this important family of chromatin effectors [31, 32], and further suggested the existence of other, yet-tobe identified protein domains, that read histone PTMs.”
The mechanisms behind the therapeutic activity of BET bromodomain inhibition (2014, background): “The human genome encodes 61 bromodomains present in 46 different proteins, where differences in the amino acid residues around the acetyl-lysine binding site impart ligand specificity (Filippakopoulos et al., 2012).”
Histone Marks in the 'Driver's Seat': Functional Roles in Steering the Transcription Cycle. (2017, background): “Bromodomain protein 4 (BRD4) is a scaffold protein containing two bromodomains, which recognize multiple acetylated residues in close proximity on histones [45].”
Single-cell RNA-seq and computational analysis using temporal mixture modelling resolves Th1/Tfh fate bifurcation in malaria (2017, background): “2 of 16 domain [named after the few proteins (namely, SP100, AIRE, NucP41/ P75, and DEAF) that have it] that interacts with DNA directly or through protein-protein interaction (23, 24), a plant homeodomain (PHD) that docks to histone methylation, and a bromodomain that binds acetylated histones (8).”
Discovery and Characterization of Super-Enhancer Associated Dependencies in Diffuse Large B-Cell Lymphoma (2013, positive): “Among the 46 known bromodomain-containing proteins (Filippakopoulos et al., 2012), the sub family of bromodomain and extra-terminal domain (BET) co-activators (BRD2, BRD3 and BRD4) are particularly appealing targets in DLBCL.”