Bromodomain
{{Pfam box
| Symbol = Bromodomain
| Name = Bromodomain
| image = 1e6i bromodomain.png
| width =
| caption = Ribbon diagram of the GCN5 bromodomain from Saccharomyces cerevisiae, colored from blue (N-terminus) to red (C-terminus).{{PDB|1e6i}}; {{cite journal |vauthors=Owen DJ, Ornaghi P, Yang JC, Lowe N, Evans PR, Ballario P, Neuhaus D, Filetici P, Travers AA | title = The structural basis for the recognition of acetylated histone H4 by the bromodomain of histone acetyltransferase gcn5p | journal = EMBO J. | volume = 19 | issue = 22 | pages = 6141–9 |date=November 2000 | pmid = 11080160 | pmc = 305837 | doi = 10.1093/emboj/19.22.6141 }}
| Pfam = PF00439
| InterPro = IPR001487
| SMART = SM00297
| PROSITE = PDOC00550
| SCOP = 1b91
| TCDB =
| OPM family =
| OPM protein =
| CDD = cd04369
| PDB = {{PDB2|1e6i}}, {{PDB2|1eqf}}, {{PDB2|1f68}}, {{PDB2|1jm4}}, {{PDB2|1jsp}}, {{PDB2|1n72}}, {{PDB2|1wug}}, {{PDB2|1wum}}, {{PDB2|1zs5}}, {{PDB2|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.{{Cite journal|last1=Ntranos|first1=Achilles|last2=Casaccia|first2=Patrizia|title=Bromodomains: Translating the words of lysine acetylation into myelin injury and repair|journal=Neuroscience Letters|volume=625|pages=4–10|doi=10.1016/j.neulet.2015.10.015|pmid=26472704|pmc=4841751|year=2016}} 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.{{cite journal | author = Zeng L, Zhou MM | title = Bromodomain: an acetyl-lysine binding domain | journal = FEBS Lett. | volume = 513 | issue = 1 | pages = 124–8 |date=February 2002 | pmid = 11911891 | doi = 10.1016/S0014-5793(01)03309-9 | s2cid = 29706103 | doi-access = }}
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.{{cite journal |vauthors=Tamkun JW, Deuring R, Scott MP, Kissinger M, Pattatucci AM, Kaufman TC, Kennison JA |title=brahma: a regulator of Drosophila homeotic genes structurally related to the yeast transcriptional activator SNF2/SWI2 |journal=Cell |volume=68 |issue=3 |pages=561–72 |date=February 1992 |pmid=1346755 |doi=10.1016/0092-8674(92)90191-E|s2cid=27726226 }} 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. Preparation, biochemical analysis, and structure determination of the bromodomain containing proteins have been described in detail.{{cite book|last1=Ren|first1=C|last2=Zeng|first2=L|last3=Zhou|first3=MM|chapter=Preparation, Biochemical Analysis, and Structure Determination of the Bromodomain, an Acetyl-Lysine Binding Domain|title=Enzymes of Epigenetics, Part A|series=Methods in Enzymology|date=2016|volume=573|pages=321–43|doi=10.1016/bs.mie.2016.01.018|pmid=27372760|isbn=9780128053652}}
={{anchor|BET protein family}}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.{{Cite journal |last=Taniguchi |first=Yasushi |date=2016-11-07 |title=The Bromodomain and Extra-Terminal Domain (BET) Family: Functional Anatomy of BET Paralogous Proteins |journal=International Journal of Molecular Sciences |volume=17 |issue=11 |pages=1849 |doi=10.3390/ijms17111849 |issn=1422-0067 |pmc=5133849 |pmid=27827996 |doi-access=free }}
=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.{{cite journal|doi=10.1016/j.cell.2012.02.013 | title=Histone Recognition and Large-Scale Structural Analysis of the Human Bromodomain Family | journal=Cell | date=2012 | volume=149 | issue=1 | pages=214–231 | first=Panagis | last=Filippakopoulos | pmid=22464331 | pmc=3326523}} Histone acetyltransferases, including EP300 and PCAF, have bromodomains in addition to acetyl-transferase domains.{{Cite journal
| pmid = 10365964
| year = 1999
| last1 = Dhalluin | first1 = C
| title = Structure and ligand of a histone acetyltransferase bromodomain
| journal = Nature | volume = 399 | issue = 6735 | pages = 491–6
| last2 = Carlson | first2 = J. E.
| last3 = Zeng | first3 = L
| last4 = He | first4 = C
| last5 = Aggarwal | first5 = A. K.
| last6 = Zhou | first6 = M. M.
| last7 = Zhou | first7 = Ming-Ming
| doi = 10.1038/20974
| s2cid = 1210925
| pmid = 17047066
| year = 2006
| last1 = Santillan | first1 = D. A.
| title = Bromodomain and histone acetyltransferase domain specificities control mixed lineage leukemia phenotype
| journal = Cancer Research
| volume = 66
| issue = 20
| pages = 10032–9
| last2 = Theisler | first2 = C. M.
| last3 = Ryan | first3 = A. S.
| last4 = Popovic | first4 = R
| last5 = Stuart | first5 = T
| last6 = Zhou | first6 = M. M.
| last7 = Alkan | first7 = S
| last8 = Zeleznik-Le | first8 = N. J.
| doi = 10.1158/0008-5472.CAN-06-2597
| doi-access = free
| pmid = 24946055
| pmc = 4183655
| year = 2014
| last1 = Hay | first1 = D. A.
| title = Discovery and optimization of small-molecule ligands for the CBP/p300 bromodomains
| journal = Journal of the American Chemical Society
| volume = 136
| issue = 26
| pages = 9308–19
| last2 = Fedorov | first2 = O
| last3 = Martin | first3 = S
| last4 = Singleton | first4 = D. C.
| last5 = Tallant | first5 = C
| last6 = Wells | first6 = C
| last7 = Picaud | first7 = S
| last8 = Philpott | first8 = M
| last9 = Monteiro | first9 = O. P.
| last10 = Rogers | first10 = C. M.
| last11 = Conway | first11 = S. J.
| last12 = Rooney | first12 = T. P.
| last13 = Tumber | first13 = A
| last14 = Yapp | first14 = C
| last15 = Filippakopoulos | first15 = P
| last16 = Bunnage | first16 = M. E.
| last17 = Müller | first17 = S
| last18 = Knapp | first18 = S
| last19 = Schofield | first19 = C. J.
| author-link19 = Christopher J. Schofield
| last20 = Brennan | first20 = P. E.
| doi = 10.1021/ja412434f
}}
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{{Cite journal |last1=Wang |first1=Nian |last2=Wu |first2=Runliu |last3=Tang |first3=Daolin |last4=Kang |first4=Rui |date=2021-01-19 |title=The BET family in immunity and disease |journal=Signal Transduction and Targeted Therapy |language=en |volume=6 |issue=1 |page=23 |doi=10.1038/s41392-020-00384-4 |pmid=33462181 |issn=2059-3635|pmc=7813845 }} and remyelination in multiple sclerosis.
Members of the BET family have been implicated as targets in both human cancer{{Cite journal|title = Targeting BET bromodomains for cancer treatment|journal = Epigenomics|date = 2015-06-16|pages = 487–501|volume = 7|issue = 3|doi = 10.2217/epi.14.91|pmid = 26077433|first1 = Marie|last1 = Jung|first2 = Kathy A|last2 = Gelato|first3 = Amaury|last3 = Fernández-Montalván|first4 = Stephan|last4 = Siegel|first5 = Bernard|last5 = Haendler}}{{Cite journal|last1=Da Costa|first1=D.|last2=Agathanggelou|first2=A.|last3=Perry|first3=T.|last4=Weston|first4=V.|last5=Petermann|first5=E.|last6=Zlatanou|first6=A.|last7=Oldreive|first7=C.|last8=Wei|first8=W.|last9=Stewart|first9=G.|date=2013-07-19|title=BET inhibition as a single or combined therapeutic approach in primary paediatric B-precursor acute lymphoblastic leukaemia|journal=Blood Cancer Journal|language=en|volume=3|issue=7|pages=e126|doi=10.1038/bcj.2013.24|pmc=3730202|pmid=23872705}} and multiple sclerosis.{{Cite journal|title = Selective Chemical Modulation of Gene Transcription Favors Oligodendrocyte Lineage Progression|journal = Chemistry & Biology|issn = 1074-5521|pmc = 4104156|pmid = 24954007|pages = 841–854|volume = 21|issue = 7|doi = 10.1016/j.chembiol.2014.05.009|first1 = Mar|last1 = Gacias|first2 = Guillermo|last2 = Gerona-Navarro|first3 = Alexander N.|last3 = Plotnikov|first4 = Guangtao|last4 = Zhang|first5 = Lei|last5 = Zeng|first6 = Jasbir|last6 = Kaur|first7 = Gregory|last7 = Moy|first8 = Elena|last8 = Rusinova|first9 = Yoel|last9 = Rodriguez|year = 2014}} BET inhibitors have shown therapeutic effects in multiple preclinical models of cancer and are currently in clinical trials in the United States.{{cite journal|doi=10.1016/j.molcel.2014.05.016 | title=The Mechanisms behind the Therapeutic Activity of BET Bromodomain Inhibition | journal=Molecular Cell | date=2014 | volume=54 | issue=5 | pages=728–736 | first=Junwei | last=Shi | pmid=24905006 | pmc=4236231}} 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.{{Cite journal
| pmid = 25864491
| pmc = 4449114
| year = 2015
| last1 = Clark
| first1 = P. G.
| title = LP99: Discovery and Synthesis of the First Selective BRD7/9 Bromodomain Inhibitor
| journal = Angewandte Chemie International Edition
| pages = 6217–21
| last2 = Vieira
| first2 = L. C.
| last3 = Tallant
| first3 = C
| last4 = Fedorov
| first4 = O
| last5 = Singleton
| first5 = D. C.
| last6 = Rogers
| first6 = C. M.
| last7 = Monteiro
| first7 = O. P.
| last8 = Bennett
| first8 = J. M.
| last9 = Baronio
| first9 = R
| last10 = Müller
| first10 = S
| last11 = Daniels
| first11 = D. L.
| last12 = Méndez
| first12 = J
| last13 = Knapp
| first13 = S
| last14 = Brennan
| first14 = P. E.
| last15 = Dixon
| first15 = D. J.
| doi = 10.1002/anie.201501394
| volume=54
| issue = 21
| pmid = 25856009
| year = 2015
| last1 = Theodoulou
| first1 = N. H.
| title = The Discovery of I-BRD9, a Selective Cell Active Chemical Probe for Bromodomain Containing Protein 9 Inhibition
| journal = Journal of Medicinal Chemistry
| volume = 59
| issue = 4
| pages = 1425–39
| last2 = Bamborough
| first2 = P
| last3 = Bannister
| first3 = A. J.
| last4 = Becher
| first4 = I
| last5 = Bit
| first5 = R. A.
| last6 = Che
| first6 = K. H.
| last7 = Chung
| first7 = C. W.
| last8 = Dittmann
| first8 = A
| last9 = Drewes
| first9 = G
| last10 = Drewry
| first10 = D. H.
| last11 = Gordon
| first11 = L
| last12 = Grandi
| first12 = P
| last13 = Leveridge
| first13 = M
| last14 = Lindon
| first14 = M
| last15 = Michon
| first15 = A. M.
| last16 = Molnar
| first16 = J
| last17 = Robson
| first17 = S. C.
| last18 = Tomkinson
| first18 = N. C.
| last19 = Kouzarides
| first19 = T
| last20 = Prinjha
| first20 = R. K.
| last21 = Humphreys
| first21 = P. G.
| doi = 10.1021/acs.jmedchem.5b00256
| pmc = 7354103
| doi-access = free
}}
See also
References
{{Reflist}}