Chromodomain & Bromodomain

Chromodomain & Bromodomain

Chromodomain

A chromodomain is a protein structural domain of about 40-50 amino acid residues commonly found in proteins associated with the remodeling and manipulation of chromatin. It is also known as chromatin organization modifier.It is first identified in Drosophila modifiers of variegation.

 The chromodomains alter the structure of chromatin to the condensed morphology of heterochromatin, a cytologically visible condition where gene expression is repressed.The domain is highly conserved among both plants and animals.It is represented in a large number of proteins found in many genomes.Some chromodomain-containing genes have multiple alternative splicing isoforms that omit the chromodomain entirely.In mammals, chromodomain-containing proteins are responsible for aspects of gene regulation related to chromatin remodeling and formation of heterochromatin regions. Chromodomain-containing proteins also bind methylated histonesand appear in the RNA-induced transcriptional silencing complex.

Proteins that contain a chromo domain appear to fall into 3 classes.

(i) The first class includes proteins having an N-terminal chromo domain followed by a region termed the chromo shadow domain, with weak but significant sequence similarity to the N-terminal chromo domain,eg. Drosophila and human heterochromatin protein Su(var)205 (HP1).

(ii) The second class includes proteins with a single chromo domain, eg. Drosophila protein Polycomb (Pc); mammalian modifier 3; human Mi-2 autoantigen and several yeast and Caenorhabditis elegans hypothetical proteins.

(iii) In the third class paired tandem chromo domains are found, eg. in mammalian DNA-binding/helicase proteins CHD-1 to CHD-4 and yeast protein CHD1.

                 Functional dissections of chromodomain proteins suggests a mechanistic role for chromo domains in targeting chromo domain proteins to specific regions of the nucleus. The mechanism of targeting may involve protein-protein and/or protein/nucleic acid interactions.

 

 

Bromodomain

Bromodomains (BRD) are small nuclear proteins that selectively bind to acetylated lysine residues of histone proteins. Once bound, these BRDs recruit protein complexes involved in chromatin structure regulation, and thus play a role in gene expression.A bromodomain is an approximately 110 amino acid protein domain that recognizes acetylated lysine residues.

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 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.

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.The name "bromodomain" is derived from the relationship of this domain with Brahma and is unrelated to the chemical element bromine.

Bromodomain-containing proteins can have a wide variety of functions, ranging from histone acetyltransferase activity and chromatin remodeling to transcriptional mediation and co-activation.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. 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.

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 in multiple sclerosis. In plants, the transition leaf shape from the juvenile to the mature phase is also regulated by bromodomain-containing proteins.