A bromodomain is a small segment of a protein that acts like a specialized “reader” within our cells. These domains are found in various proteins throughout the body. Their fundamental role involves recognizing specific molecular tags, enabling them to play a part in many biological processes.
The Molecular Structure and Its Function
A bromodomain is a protein domain composed of a bundle of four alpha-helices, separated by loop regions. These helices and loops create a hydrophobic pocket, which is the specific binding site.
This pocket’s primary function is to recognize and bind to acetylated lysine residues. Acetylation is a chemical modification where an acetyl group is added to a lysine amino acid, often on histones. This acetylation acts as a molecular “tag” that bromodomains detect.
Histone proteins are the spools around which DNA is wrapped. When a lysine residue on a histone protein becomes acetylated, the bromodomain binds to this specific acetylated lysine. This binding is a prerequisite for protein-histone interactions and changes in chromatin structure.
How Bromodomains Control Our Genes
Bromodomains play a role in regulating gene expression by binding to acetylated lysines. When a bromodomain-containing protein binds to an acetylated histone, it can influence the structure of chromatin, the complex of DNA and proteins that forms chromosomes. Acetylation of histones is associated with an “open” chromatin state, which makes DNA more accessible for gene transcription.
Bromodomains are “epigenetic readers” that interpret these acetylation marks. By binding to acetylated histones, they can recruit other proteins and molecular machinery to specific regions of DNA. This recruitment can either activate or suppress gene transcription. This process influences various cellular functions and developmental pathways.
Bromodomains and Human Health
Dysregulated bromodomains can contribute to various health conditions by leading to aberrant gene activity and promoting disease progression. For instance, certain bromodomain-containing proteins, like BRD4, have been linked to specific types of cancer.
In cancer, bromodomain proteins are often overexpressed or mutated, driving tumor growth and proliferation. For example, chromosomal translocations involving BRD3 and BRD4 genes are associated with rare cancers like NUT midline carcinoma. Bromodomains are also implicated in inflammatory diseases, where their dysregulation can contribute to the inflammatory response.
New Medicines Targeting Bromodomains
Understanding bromodomains’ role in disease has led to new drug discovery efforts, with scientists designing “bromodomain inhibitors” that aim to block the binding pocket of these proteins. These inhibitors, such as BET (bromodomain and extra-terminal) inhibitors, prevent bromodomains from recognizing acetylated lysine residues.
By disrupting this binding, inhibitors interfere with the proteins’ disease-causing activity. For example, BET inhibitors have shown promise in preclinical models and are in clinical trials for various cancers, including hematological malignancies and solid tumors. Research is also exploring their potential in treating inflammatory conditions and other diseases, representing a new avenue in therapeutic development.