Bromodomain

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Bromodomain
1e6i bromodomain.png
Ribbon diagram of the GCN5 bromodomain from Saccharomyces cerevisiae , colored from blue (N-terminus) to red (C-terminus). [1]
Identifiers
SymbolBromodomain
Pfam PF00439
InterPro IPR001487
SMART SM00297
PROSITE PDOC00550
SCOP2 1b91 / SCOPe / SUPFAM
CDD cd04369
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary
PDB 1e6i ​, 1eqf ​, 1f68 ​, 1jm4 ​, 1jsp ​, 1n72 ​, 1wug ​, 1wum ​, 1zs5 ​, 2d82 ​

A bromodomain is an approximately 110 amino acid protein domain that recognizes acetylated lysine residues, such as those on the N-terminal tails of histones. Bromodomains, as the "readers" of lysine acetylation, are responsible in transducing the signal carried by acetylated lysine residues and translating it into various normal or abnormal phenotypes. [2] Their affinity is higher for regions where multiple acetylation sites exist in proximity. This recognition is often a prerequisite for protein-histone association and chromatin remodeling. The domain itself adopts an all-α protein fold, a bundle of four alpha helices each separated by loop regions of variable lengths that form a hydrophobic pocket that recognizes the acetyl lysine. [1] [3]

Contents

Discovery

The bromodomain was identified as a novel structural motif by John W. Tamkun and colleagues studying the Drosophila gene Brahma /brm, and showed sequence similarity to genes involved in transcriptional activation. [4] The name "bromodomain" is derived from the relationship of this domain with Brahma and is unrelated to the chemical element bromine.

Bromodomain-containing proteins

Bromodomain-containing proteins can have a wide variety of functions, ranging from histone acetyltransferase activity and chromatin remodeling to transcriptional mediation and co-activation. Of the 43 known in 2015, 11 had two bromodomains, and one protein had 6 bromodomains. [2] Preparation, biochemical analysis, and structure determination of the bromodomain containing proteins have been described in detail. [5]

Bromo- and Extra-Terminal domain (BET) family

A well-known example of a bromodomain family is the BET (Bromodomain and extraterminal domain) family. Members of this family include BRD2, BRD3, BRD4 and BRDT. [6]

Other

However proteins such as ASH1L also contain a bromodomain. Dysfunction of BRD proteins has been linked to diseases such as human squamous cell carcinoma and other forms of cancer. [7] Histone acetyltransferases, including EP300 and PCAF, have bromodomains in addition to acetyl-transferase domains. [8] [9] [10]

Not considered part of the BET family (yet containing a bromodomain) are BRD7, and BRD9.

Role in human disease

The role of bromodomains in translating a deregulated cell acetylome into disease phenotypes was recently unveiled by the development of small molecule bromodomain inhibitors. This breakthrough discovery highlighted bromodomain-containing proteins as key players in cancer biology, as well as inflammation [11] and remyelination in multiple sclerosis. [2]

Members of the BET family have been implicated as targets in both human cancer [12] [13] and multiple sclerosis. [14] BET inhibitors have shown therapeutic effects in multiple preclinical models of cancer and are currently in clinical trials in the United States. [15] Their application in multiple sclerosis is still in the preclinical stage.

Small molecule inhibitors of non-BET bromodomain proteins BRD7 and BRD9 have also been developed. [16] [17]

See also

Related Research Articles

<span class="mw-page-title-main">Histone acetyltransferase</span> Enzymes that catalyze acyl group transfer from acetyl-CoA to histones

Histone acetyltransferases (HATs) are enzymes that acetylate conserved lysine amino acids on histone proteins by transferring an acetyl group from acetyl-CoA to form ε-N-acetyllysine. DNA is wrapped around histones, and, by transferring an acetyl group to the histones, genes can be turned on and off. In general, histone acetylation increases gene expression.

<span class="mw-page-title-main">Histone deacetylase</span> Class of enzymes important in regulating DNA transcription

Histone deacetylases (EC 3.5.1.98, HDAC) are a class of enzymes that remove acetyl groups (O=C-CH3) from an ε-N-acetyl lysine amino acid on both histone and non-histone proteins. HDACs allow histones to wrap the DNA more tightly. This is important because DNA is wrapped around histones, and DNA expression is regulated by acetylation and de-acetylation. HDAC's action is opposite to that of histone acetyltransferase. HDAC proteins are now also called lysine deacetylases (KDAC), to describe their function rather than their target, which also includes non-histone proteins. In general, they suppress gene expression.

<span class="mw-page-title-main">Coactivator (genetics)</span> Class of proteins involved in regulation of transcription

A coactivator is a type of transcriptional coregulator that binds to an activator to increase the rate of transcription of a gene or set of genes. The activator contains a DNA binding domain that binds either to a DNA promoter site or a specific DNA regulatory sequence called an enhancer. Binding of the activator-coactivator complex increases the speed of transcription by recruiting general transcription machinery to the promoter, therefore increasing gene expression. The use of activators and coactivators allows for highly specific expression of certain genes depending on cell type and developmental stage.

<span class="mw-page-title-main">PCAF</span> Protein-coding gene in the species Homo sapiens

P300/CBP-associated factor (PCAF), also known as K(lysine) acetyltransferase 2B (KAT2B), is a human gene and transcriptional coactivator associated with p53.

<span class="mw-page-title-main">CREB-binding protein</span> Nuclear protein that binds to CREB

CREB-binding protein, also known as CREBBP or CBP or KAT3A, is a coactivator encoded by the CREBBP gene in humans, located on chromosome 16p13.3. CBP has intrinsic acetyltransferase functions; it is able to add acetyl groups to both transcription factors as well as histone lysines, the latter of which has been shown to alter chromatin structure making genes more accessible for transcription. This relatively unique acetyltransferase activity is also seen in another transcription enzyme, EP300 (p300). Together, they are known as the p300-CBP coactivator family and are known to associate with more than 16,000 genes in humans; however, while these proteins share many structural features, emerging evidence suggests that these two co-activators may promote transcription of genes with different biological functions.

<span class="mw-page-title-main">Histone acetylation and deacetylation</span>

Histone acetylation and deacetylation are the processes by which the lysine residues within the N-terminal tail protruding from the histone core of the nucleosome are acetylated and deacetylated as part of gene regulation.

Chromatin remodeling is the dynamic modification of chromatin architecture to allow access of condensed genomic DNA to the regulatory transcription machinery proteins, and thereby control gene expression. Such remodeling is principally carried out by 1) covalent histone modifications by specific enzymes, e.g., histone acetyltransferases (HATs), deacetylases, methyltransferases, and kinases, and 2) ATP-dependent chromatin remodeling complexes which either move, eject or restructure nucleosomes. Besides actively regulating gene expression, dynamic remodeling of chromatin imparts an epigenetic regulatory role in several key biological processes, egg cells DNA replication and repair; apoptosis; chromosome segregation as well as development and pluripotency. Aberrations in chromatin remodeling proteins are found to be associated with human diseases, including cancer. Targeting chromatin remodeling pathways is currently evolving as a major therapeutic strategy in the treatment of several cancers.

<span class="mw-page-title-main">KAT2A</span> Protein-coding gene in the species Homo sapiens

Histone acetyltransferase KAT2A is an enzyme that in humans is encoded by the KAT2A gene.

In enzymology, an alpha-tubulin N-acetyltransferase is an enzyme which is encoded by the ATAT1 gene.

<span class="mw-page-title-main">BRD4</span> Protein-coding gene in the species Homo sapiens

Bromodomain-containing protein 4 is a protein that in humans is encoded by the BRD4 gene.

<span class="mw-page-title-main">KAT8</span> Protein-coding gene in the species Homo sapiens

K(lysine) acetyltransferase 8 (KAT8) is an enzyme that in humans is encoded by the KAT8 gene.

<span class="mw-page-title-main">Bromodomain-containing protein 3</span> Protein-coding gene in the species Homo sapiens

Bromodomain-containing protein 3 (BRD3) also known as RING3-like protein (RING3L) is a protein that in humans is encoded by the BRD3 gene. This gene was identified based on its homology to the gene encoding the RING3 (BRD2) protein, a serine/threonine kinase. The gene maps to 9q34, a region which contains several major histocompatibility complex (MHC) genes.

<span class="mw-page-title-main">Ming-Ming Zhou</span>

Ming-Ming Zhou is an American scientist who focuses on structural and chemical biology, NMR spectroscopy, and drug design. He is the Dr. Harold and Golden Lamport Professor and Chairman of the Department of Pharmacological Sciences. He is also the co-director of the Drug Discovery Institute at the Icahn School of Medicine at Mount Sinai and Mount Sinai Health System in New York City, as well as Professor of Sciences. Zhou is an elected fellow of the American Association for the Advancement of Science.

Protein acetylation are acetylation reactions that occur within living cells as drug metabolism, by enzymes in the liver and other organs. Pharmaceuticals frequently employ acetylation to enable such esters to cross the blood–brain barrier, where they are deacetylated by enzymes (carboxylesterases) in a manner similar to acetylcholine. Examples of acetylated pharmaceuticals are diacetylmorphine (heroin), acetylsalicylic acid (aspirin), THC-O-acetate, and diacerein. Conversely, drugs such as isoniazid are acetylated within the liver during drug metabolism. A drug that depends on such metabolic transformations in order to act is termed a prodrug.

BET inhibitors are a class of drugs that reversibly bind the bromodomains of Bromodomain and Extra-Terminal motif (BET) proteins BRD2, BRD3, BRD4, and BRDT, and prevent protein-protein interaction between BET proteins and acetylated histones and transcription factors.

<span class="mw-page-title-main">Brpf1</span> Protein-coding gene in the species Mus musculus

Peregrin also known as bromodomain and PHD finger-containing protein 1 is a protein that in humans is encoded by the BRPF1 gene located on 3p26-p25. Peregrin is a multivalent chromatin regulator that recognizes different epigenetic marks and activates three histone acetyltransferases. BRPF1 contains two PHD fingers, one bromodomain and one chromo/Tudor-related Pro-Trp-Trp-Pro (PWWP) domain.

H4K5ac is an epigenetic modification to the DNA packaging protein histone H4. It is a mark that indicates the acetylation at the 5th lysine residue of the histone H4 protein. H4K5 is the closest lysine residue to the N-terminal tail of histone H4. It is enriched at the transcription start site (TSS) and along gene bodies. Acetylation of histone H4K5 and H4K12ac is enriched at centromeres.

H4K12ac is an epigenetic modification to the DNA packaging protein histone H4. It is a mark that indicates the acetylation at the 12th lysine residue of the histone H4 protein. H4K12ac is involved in learning and memory. It is possible that restoring this modification could reduce age-related decline in memory.

H4K91ac is an epigenetic modification to the DNA packaging protein histone H4. It is a mark that indicates the acetylation at the 91st lysine residue of the histone H4 protein. No known diseases are attributed to this mark but it might be implicated in melanoma.

H3K9ac is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the acetylation at the 9th lysine residue of the histone H3 protein.

References

  1. 1 2 PDB: 1e6i ​; Owen DJ, Ornaghi P, Yang JC, Lowe N, Evans PR, Ballario P, Neuhaus D, Filetici P, Travers AA (November 2000). "The structural basis for the recognition of acetylated histone H4 by the bromodomain of histone acetyltransferase gcn5p". EMBO J. 19 (22): 6141–9. doi:10.1093/emboj/19.22.6141. PMC   305837 . PMID   11080160.
  2. 1 2 3 Ntranos, Achilles; Casaccia, Patrizia (2016). "Bromodomains: Translating the words of lysine acetylation into myelin injury and repair". Neuroscience Letters. 625: 4–10. doi:10.1016/j.neulet.2015.10.015. PMC   4841751 . PMID   26472704.
  3. ↑ Zeng L, Zhou MM (February 2002). "Bromodomain: an acetyl-lysine binding domain". FEBS Lett. 513 (1): 124–8. doi:10.1016/S0014-5793(01)03309-9. PMID   11911891. S2CID   29706103.
  4. ↑ Tamkun JW, Deuring R, Scott MP, Kissinger M, Pattatucci AM, Kaufman TC, Kennison JA (February 1992). "brahma: a regulator of Drosophila homeotic genes structurally related to the yeast transcriptional activator SNF2/SWI2". Cell. 68 (3): 561–72. doi:10.1016/0092-8674(92)90191-E. PMID   1346755. S2CID   27726226.
  5. ↑ Ren, C; Zeng, L; Zhou, MM (2016). Preparation, Biochemical Analysis, and Structure Determination of the Bromodomain, an Acetyl-Lysine Binding Domain. Methods in Enzymology. Vol. 573. pp. 321–43. doi:10.1016/bs.mie.2016.01.018. ISBN   9780128053652. PMID   27372760.
  6. ↑ Taniguchi, Yasushi (2016-11-07). "The Bromodomain and Extra-Terminal Domain (BET) Family: Functional Anatomy of BET Paralogous Proteins". International Journal of Molecular Sciences. 17 (11): 1849. doi: 10.3390/ijms17111849 . ISSN   1422-0067. PMC   5133849 . PMID   27827996.
  7. ↑ Filippakopoulos, Panagis (2012). "Histone Recognition and Large-Scale Structural Analysis of the Human Bromodomain Family". Cell. 149 (1): 214–231. doi:10.1016/j.cell.2012.02.013. PMC   3326523 . PMID   22464331.
  8. ↑ Dhalluin, C; Carlson, J. E.; Zeng, L; He, C; Aggarwal, A. K.; Zhou, M. M.; Zhou, Ming-Ming (1999). "Structure and ligand of a histone acetyltransferase bromodomain". Nature. 399 (6735): 491–6. doi:10.1038/20974. PMID   10365964. S2CID   1210925.
  9. ↑ Santillan, D. A.; Theisler, C. M.; Ryan, A. S.; Popovic, R; Stuart, T; Zhou, M. M.; Alkan, S; Zeleznik-Le, N. J. (2006). "Bromodomain and histone acetyltransferase domain specificities control mixed lineage leukemia phenotype". Cancer Research. 66 (20): 10032–9. doi: 10.1158/0008-5472.CAN-06-2597 . PMID   17047066.
  10. ↑ Hay, D. A.; Fedorov, O; Martin, S; Singleton, D. C.; Tallant, C; Wells, C; Picaud, S; Philpott, M; Monteiro, O. P.; Rogers, C. M.; Conway, S. J.; Rooney, T. P.; Tumber, A; Yapp, C; Filippakopoulos, P; Bunnage, M. E.; Müller, S; Knapp, S; Schofield, C. J.; Brennan, P. E. (2014). "Discovery and optimization of small-molecule ligands for the CBP/p300 bromodomains". Journal of the American Chemical Society. 136 (26): 9308–19. doi:10.1021/ja412434f. PMC   4183655 . PMID   24946055.
  11. ↑ Wang, Nian; Wu, Runliu; Tang, Daolin; Kang, Rui (2021-01-19). "The BET family in immunity and disease". Signal Transduction and Targeted Therapy. 6 (1): 23. doi:10.1038/s41392-020-00384-4. ISSN   2059-3635. PMC   7813845 . PMID   33462181.
  12. ↑ Jung, Marie; Gelato, Kathy A; Fernández-Montalván, Amaury; Siegel, Stephan; Haendler, Bernard (2015-06-16). "Targeting BET bromodomains for cancer treatment". Epigenomics. 7 (3): 487–501. doi:10.2217/epi.14.91. PMID   26077433.
  13. ↑ Da Costa, D.; Agathanggelou, A.; Perry, T.; Weston, V.; Petermann, E.; Zlatanou, A.; Oldreive, C.; Wei, W.; Stewart, G. (2013-07-19). "BET inhibition as a single or combined therapeutic approach in primary paediatric B-precursor acute lymphoblastic leukaemia". Blood Cancer Journal. 3 (7): e126. doi:10.1038/bcj.2013.24. PMC   3730202 . PMID   23872705.
  14. ↑ Gacias, Mar; Gerona-Navarro, Guillermo; Plotnikov, Alexander N.; Zhang, Guangtao; Zeng, Lei; Kaur, Jasbir; Moy, Gregory; Rusinova, Elena; Rodriguez, Yoel (2014). "Selective Chemical Modulation of Gene Transcription Favors Oligodendrocyte Lineage Progression". Chemistry & Biology. 21 (7): 841–854. doi:10.1016/j.chembiol.2014.05.009. ISSN   1074-5521. PMC   4104156 . PMID   24954007.
  15. ↑ Shi, Junwei (2014). "The Mechanisms behind the Therapeutic Activity of BET Bromodomain Inhibition". Molecular Cell. 54 (5): 728–736. doi:10.1016/j.molcel.2014.05.016. PMC   4236231 . PMID   24905006.
  16. ↑ Clark, P. G.; Vieira, L. C.; Tallant, C; Fedorov, O; Singleton, D. C.; Rogers, C. M.; Monteiro, O. P.; Bennett, J. M.; Baronio, R; Müller, S; Daniels, D. L.; Méndez, J; Knapp, S; Brennan, P. E.; Dixon, D. J. (2015). "LP99: Discovery and Synthesis of the First Selective BRD7/9 Bromodomain Inhibitor". Angewandte Chemie International Edition. 54 (21): 6217–21. doi:10.1002/anie.201501394. PMC   4449114 . PMID   25864491.
  17. ↑ Theodoulou, N. H.; Bamborough, P; Bannister, A. J.; Becher, I; Bit, R. A.; Che, K. H.; Chung, C. W.; Dittmann, A; Drewes, G; Drewry, D. H.; Gordon, L; Grandi, P; Leveridge, M; Lindon, M; Michon, A. M.; Molnar, J; Robson, S. C.; Tomkinson, N. C.; Kouzarides, T; Prinjha, R. K.; Humphreys, P. G. (2015). "The Discovery of I-BRD9, a Selective Cell Active Chemical Probe for Bromodomain Containing Protein 9 Inhibition". Journal of Medicinal Chemistry. 59 (4): 1425–39. doi: 10.1021/acs.jmedchem.5b00256 . PMC   7354103 . PMID   25856009.
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