A bromodomain is an approximately 110 amino acid

protein domain In molecular biology, a protein domain is a region of a protein's polypeptide chain that is self-stabilizing and that folds independently from the rest. Each domain forms a compact folded three-dimensional structure. Many proteins consist of ...

that recognizes acetylated

lysine Lysine (symbol Lys or K) is an α-amino acid that is a precursor to many proteins. It contains an α-amino group (which is in the protonated form under biological conditions), an α-carboxylic acid group (which is in the deprotonated − ...

residues, such as those on the ''N''-terminal tails of

histone In biology, histones are highly basic proteins abundant in lysine and arginine residues that are found in eukaryotic cell nuclei. They act as spools around which DNA winds to create structural units called nucleosomes. Nucleosomes in turn a ...

s. 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. 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 Chromatin is a complex of DNA and protein found in eukaryote, eukaryotic cells. The primary function is to package long DNA molecules into more compact, denser structures. This prevents the strands from becoming tangled and also plays important ...

remodeling. The domain itself adopts an

all-α protein fold In molecular biology, protein fold classes are broad categories of protein tertiary structure topology. They describe groups of proteins that share similar amino acid and secondary structure proportions. Each class contains multiple, independent ...

, a bundle of four

alpha helices The alpha helix (α-helix) is a common motif in the secondary structure of proteins and is a right hand-helix conformation in which every backbone N−H group hydrogen bonds to the backbone C=O group of the amino acid located four residues ear ...

each separated by loop regions of variable lengths that form a hydrophobic pocket that recognizes the acetyl lysine.

Discovery

The bromodomain was identified as a novel

structural motif In a chain-like biological molecule, such as a protein or nucleic acid, a structural motif is a common three-dimensional structure that appears in a variety of different, evolutionarily unrelated molecules. A structural motif does not have t ...

by John W. Tamkun and colleagues studying the

drosophila ''Drosophila'' () is a genus of flies, belonging to the family Drosophilidae, whose members are often called "small fruit flies" or (less frequently) pomace flies, vinegar flies, or wine flies, a reference to the characteristic of many speci ...

gene ''

Brahma Brahma ( sa, ब्रह्मा, Brahmā) is a Hindu god, referred to as "the Creator" within the Trimurti, the trinity of supreme divinity that includes Vishnu, and Shiva.Jan Gonda (1969)The Hindu Trinity Anthropos, Bd 63/64, H 1/2, pp ...

''/''brm'', and showed sequence similarity to genes involved in transcriptional activation. The name "bromodomain" is derived from the relationship of this domain with ''Brahma'' and is unrelated to the chemical element

bromine Bromine is a chemical element with the symbol Br and atomic number 35. It is the third-lightest element in group 17 of the periodic table ( halogens) and is a volatile red-brown liquid at room temperature that evaporates readily to form a simi ...

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.

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 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/th ...

BRD4 Bromodomain-containing protein 4 is a protein that in humans is encoded by the ''BRD4'' gene. BRD4 is a member of the BET (bromodomain and extra terminal domain) family, which also includes BRD2, BRD3, and BRDT. BRD4, similar to other BET fami ...

and

BRDT Bromodomain testis-specific protein is a protein that in humans is encoded by the ''BRDT'' gene. It is a member of the Bromodomain and Extra-terminal motif (BET) protein family. BRDT is similar to the RING3 protein family. It possesses 2 bromo ...

Other

However proteins such as

ASH1L ASH1L (also called huASH1, ASH1, ASH1L1, ASH1-like, or KMT2H) is a histone-lysine N-methyltransferase enzyme encoded by the ASH1L gene located at chromosomal band 1q22. ASH1L is the human homolog of Drosophila Ash1 (absent, small, or homeotic-lik ...

also contain a bromodomain. Dysfunction of BRD proteins has been linked to diseases such as human squamous cell carcinoma and other forms of cancer. Histone acetyltransferases, including

EP300 Histone acetyltransferase p300 also known as p300 HAT or E1A-associated protein p300 (where E1A = adenovirus early region 1A) also known as EP300 or p300 is an enzyme that, in humans, is encoded by the ''EP300'' gene. It functions as histone acet ...

and

PCAF P300/CBP-associated factor (PCAF), also known as K(lysine) acetyltransferase 2B (KAT2B), is a human gene and transcriptional coactivator associated with p53. Structure Several domains of PCAF can act independently or in unison to enable its funct ...

, have bromodomains in addition to acetyl-transferase domains. Not considered part of the BET family (yet containing a bromodomain) are

BRD7 Bromodomain-containing protein 7 is a protein that in humans is encoded by the ''BRD7'' gene. Interactions BRD7 has been shown to interact with IRF2 and HNRPUL1. Azoospermia BRD7 protein is a transcription regulator that is normally highly e ...

, and

BRD9 Bromodomain-containing protein 9 is a protein that in humans is encoded by the ''BRD9'' gene. Structure and interaction BRD9 contains a bromodomain. It is closely related to BRD7. BRD9 is present in some SWI/SNF ATPase remodeling complexes. Ro ...

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 and

remyelination Remyelination is the process of propagating oligodendrocyte precursor cells to form oligodendrocytes to create new myelin sheaths on demyelinated axons in the CNS. This is a process naturally regulated in the body and tends to be very efficient i ...

multiple sclerosis Multiple (cerebral) sclerosis (MS), also known as encephalomyelitis disseminata or disseminated sclerosis, is the most common demyelinating disease, in which the insulating covers of nerve cells in the brain and spinal cord are damaged. This ...

. Members of the BET family have been implicated as targets in both human cancer and multiple sclerosis. BET inhibitors have shown therapeutic effects in multiple preclinical models of cancer and are currently in clinical trials in the United States. Their application in multiple sclerosis is still in the preclinical stage. Small molecule inhibitors of non-BET bromodomain proteins

and

have also been developed.

References