The bromodomain interaction module

Filippakopoulos, P.; Knapp, Stefan

doi:10.1016/j.febslet.2012.04.045

Cited by 336 publications

(415 citation statements)

References 112 publications

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“…2, H-J). Several bromodomain proteins harbor YN residues in their active site (46). We found that ZMYND8 has Tyr-Y227 and Asn-228 amino acids in its bromodomain, which are absent in ZMYND11.…”

Section: Discussionmentioning

confidence: 76%

Selective Recognition of H3.1K36 Dimethylation/H4K16 Acetylation Facilitates the Regulation of All-trans-retinoic Acid (ATRA)-responsive Genes by Putative Chromatin Reader ZMYND8

Adhikary

Sanyal

Basu

et al. 2016

Journal of Biological Chemistry

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ZMYND8 (zinc finger MYND (Myeloid, Nervy and DEAF-1)-type containing 8), a newly identified component of the transcriptional coregulator network, was found to interact with the Nucleosome Remodeling and Deacetylase (NuRD) complex. Previous reports have shown that ZMYND8 is instrumental in recruiting the NuRD complex to damaged chromatin for repressing transcription and promoting double strand break repair by homologous recombination. However, the mode of transcription regulation by ZMYND8 has remained elusive. Here, we report that through its specific key residues present in its conserved chromatin-binding modules, ZMYND8 interacts with the selective epigenetic marks H3.1K36Me2/H4K16Ac. Furthermore, ZMYND8 shows a clear preference for canonical histone H3.1 over variant H3.3. Interestingly, ZMYND8 was found to be recruited to several developmental genes, including the all-trans-retinoic acid (ATRA)-responsive ones, through its modified histone-binding ability. Being itself inducible by ATRA, this zinc finger transcription factor is involved in modulating other ATRA-inducible genes. We found that ZMYND8 interacts with transcription initiation-competent RNA polymerase II phosphorylated at Ser-5 in a DNA templatedependent manner and can alter the global gene transcription. Overall, our study identifies that ZMYND8 has CHD4-independent functions in regulating gene expression through its modified histone-binding ability.ZMYND8 (zinc finger MYND (Myeloid, Nervy and DEAF-1)-type containing 8) is a putative chromatin reader/effector harboring a PWWP domain, a bromodomain, and a PHD type zinc finger. It associates with the CHD4 protein of NuRD chromatin remodeling complex implicated in gene transcription, cell cycle progression, and genome integrity (1, 2). Reader proteins specifically recognize histone post-translational modifications (PTMs) 5 and translate such recognition(s) into meaningful biological outcomes by virtue of either their intrinsic activities or those of their interacting partners (3). These readers may interpret histone PTMs via "monovalent" or "multivalent" recognition (4). In monovalent recognition, a chromatin reader recognizes one histone PTM. In contrast, in multivalent recognition, readers recognize multiple histone modifications intra/inter-nucleosomally. An accessible surface is provided by these readers (such as a cavity or surface groove), which accommodates the modified histone residues, and determines the modification (e.g. acetylation versus methylation) or state specificity (such as mono-versus trimethylation of lysine) (3).ZMYND8 is a well known component of the transcription coregulator complex and is associated with several demethylase machinery components, including KDM5A, KDM5C, or LSD1 (5, 6). Through its ability to interact with Xenopus RCoR2, ZMYND8 plays a significant role in embryonic neural differentiation (7). Apart from this, ZMYND8 is also involved in T-cell lymphoma and breast and cervical cancer (8 -10). Another interesting feature is that ZMYND8 is significantly involved...

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Section: Discussionmentioning

confidence: 76%

Selective Recognition of H3.1K36 Dimethylation/H4K16 Acetylation Facilitates the Regulation of All-trans-retinoic Acid (ATRA)-responsive Genes by Putative Chromatin Reader ZMYND8

Adhikary

Sanyal

Basu

et al. 2016

Journal of Biological Chemistry

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“…The same rationale can be exploited for intra-family selectivity: for example, PRKCBP1 was predicted to have a particularly unstable water network (Fig. 2a), contrary to other proteins in the same family, TAF1(1), TAF1(2), and TAF1L (2). Similarly, BRD4(1) and BRDT (1) appeared to have more weakly bound water molecules when compared to other bromodomains in Family II, and this may provide a strategy for the selective targeting and thus further study of these bromodomains with established pharmacological interest 31 .…”

Section: General Approachmentioning

confidence: 95%

“…romodomains are small protein modules that recognize acetylated lysine on histones, and are involved in the epigenetic regulation of gene expression 1,2 . Given their connection to a number of diseases, including cancer, inflammation, and viral infection, they have recently been the subject of intense efforts for the development of chemical probes aimed at their validation as drug targets [3][4][5][6] .…”

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confidence: 99%

“…Cox et al 14 noticed the displacement of W1 from the binding pocket of PHIP(2) (in Family III) by a thiourea fragment, while Zhu and Caflisch 15 reported the displacement of W1 from BRPF1 (a member of Family IV) by an isoquinolinone fragment. Recently, Crawford et al 16 described the discovery of ligands causing a rearrangement of the water network in BRD4(1) and TAF1 (2) and the displacement of W3 and W4. The same behavior of TAF1 (2) was previously observed also by Flynn et al 17 while investigating bromodomain recognition of butyryllysine and crotonyllysine.…”

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confidence: 99%

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Large-scale analysis of water stability in bromodomain binding pockets with grand canonical Monte Carlo

et al. 2018

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Conserved water molecules are of interest in drug design, as displacement of such waters can lead to higher affinity ligands, and in some cases, contribute towards selectivity. Bromodomains, small protein domains involved in the epigenetic regulation of gene transcription, display a network of four conserved water molecules in their binding pockets and have recently been the focus of intense medicinal chemistry efforts. Understanding why certain bromodomains have displaceable water molecules and others do not is extremely challenging, and it remains unclear which water molecules in a given bromodomain can be targeted for displacement. Here we estimate the stability of the conserved water molecules in 35 bromodomains via binding free energy calculations using all-atom grand canonical Monte Carlo simulations. Encouraging quantitative agreement to the available experimental evidence is found. We thus discuss the expected ease of water displacement in different bromodomains and the implications for ligand selectivity.

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“…For example, the bromodomain is the specific reader module for acetylated lysines on histones and nonhistone proteins (reviewed in ref. 2), where acetylation is one of the most abundant posttranslational modifications in human cells.…”

mentioning

confidence: 99%

Binding of the histone chaperone ASF1 to the CBP bromodomain promotes histone acetylation

Das

Roy

Namjoshi

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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The multifunctional Creb-binding protein (CBP) protein plays a pivotal role in many critical cellular processes. Here we demonstrate that the bromodomain of CBP binds to histone H3 acetylated on lysine 56 (K56Ac) with higher affinity than to its other monoacetylated binding partners. We show that autoacetylation of CBP is critical for the bromodomain-H3 K56Ac interaction, and we propose that this interaction occurs via autoacetylation-induced conformation changes in CBP. Unexpectedly, the bromodomain promotes acetylation of H3 K56 on free histones. The CBP bromodomain also interacts with the histone chaperone anti-silencing function 1 (ASF1) via a nearby but distinct interface. This interaction is necessary for ASF1 to promote acetylation of H3 K56 by CBP, indicating that the ASF1-bromodomain interaction physically delivers the histones to the histone acetyl transferase domain of CBP. A CBP bromodomain mutation manifested in Rubinstein-Taybi syndrome has compromised binding to both H3 K56Ac and ASF1, suggesting that these interactions are important for the normal function of CBP. C hromatin is the physiological template for all genomic processes. The histone proteins that package the DNA into chromatin are subject to posttranslational modifications, including acetylation, methylation, phosphorylation, ubiquitination, and sumoylation, that serve to regulate DNA-templated phenomena such as transcription, replication, repair, and recombination (1). Many histone posttranslational modifications mediate their function by interacting specifically with and recruiting "reader" modules of multifunctional proteins, which often themselves have activities that subsequently further modify the chromatin structure to make the DNA either more or less accessible. For example, the bromodomain is the specific reader module for acetylated lysines on histones and nonhistone proteins (reviewed in ref.2), where acetylation is one of the most abundant posttranslational modifications in human cells.The bromodomain is found in many transcriptional coregulators and histone-modifying complexes, including histone acetyl transferases (HATs), enzymes that themselves mediate acetylation. Structural studies have revealed that bromodomains have a conserved structural fold that consists of a left-handed four-helix bundle and two interspersed ZA and BC loops which constitute the active acetyl lysine-binding pocket (3). Despite this conserved overall structure, different bromodomains recognize distinct acetylated lysines in different proteins because the specific amino acid residues within the loops of each bromodomain are critical for determining the acetyl lysine-binding specificity (4, 5).The general theme for bromodomain function is that they serve to anchor the bromodomain-containing protein to acetylated chromatin templates or to acetylated transcriptional activators. For example, the bromodomains of the yeast ATP-dependent nucleosome remodeler Swi2 and the HAT GCN5 are required for anchoring these chromatin-modifying complexes to acetylated c...

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The bromodomain interaction module

Cited by 336 publications

References 112 publications

Selective Recognition of H3.1K36 Dimethylation/H4K16 Acetylation Facilitates the Regulation of All-trans-retinoic Acid (ATRA)-responsive Genes by Putative Chromatin Reader ZMYND8

Selective Recognition of H3.1K36 Dimethylation/H4K16 Acetylation Facilitates the Regulation of All-trans-retinoic Acid (ATRA)-responsive Genes by Putative Chromatin Reader ZMYND8

Large-scale analysis of water stability in bromodomain binding pockets with grand canonical Monte Carlo

Binding of the histone chaperone ASF1 to the CBP bromodomain promotes histone acetylation

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