Bromodomain (BRD) Family

Authors

Creative Biogene

Summary

Acetylation of lysine residues is a widespread protein post-translational modification (PTM), and extensively relevant to modulation of cellular processes, including protein conformation and interaction. Histone lysine acetylation was historically proposed to be a hallmark of transcriptionally active genes, and so far, deregulation of histone acetylation patterns often drives the aberrant expression of oncogenes leading to proliferation and tumorigenesis. Three types of proteins have been identified to regulate lysine acetylation: histone acetyltransferases (HATs), bromodomain (BRD) proteins, histone deacetylases (HDACs) and sirtuins (SIRTs). Bromodomains, acting as acetyl-lysine binding domains, belong to a family of evolutionarily conserved protein modules that originally are found in proteins associated with chromatin and in almost all nuclear HATs. BRDs could contribute to highly specific histone acetylation through tethering transcriptional HATs to specific chromosomal sites, or to the activity of multi-protein complexes in chromatin remodeling. Therefore, BRDs modulate enzyme activities, protein assembly and protein-protein interactions (PPIs) through lysine acetylation, revealing wide implications for the mechanisms underlying a broad variety of cellular events, such as chromatin remodeling and transcriptional activation.

Introduction

BRDs are 110 amino acid modules which are highly conserved throughout evolution. The BRD-containing protein family includes a variety of transcriptional coregulators, chromatin modifying enzymes and nuclear scaffold proteins that are able to specifically recognize acetylated lysine residues on histone tails. BRD containing proteins are able to also bind acetylated lysine residues on non-histone proteins. The BRD structure is composed of a left-handed bundle of four antiparallel alpha helices linked by two loop regions (Figure 1). The co-crystal structures of BRDs bound to acetyl-lysine containing peptides suggest that the acetylated lysine is first recognized in a hydrophobic pocket located between the two loops, which are formed by the most highly conserved residues. This includes an asparagine at the core of the binding site, which engages the acetyl-lysine through a hydrogen bond between its NH2 group and the acetyl carbonyl oxygen atom of the acetylated lysine. At the entrance of the binding pocket, residues located in the two loop regions interact with residues adjacent to the acetylated lysine in the target sequence, and further reinforcing the binding through hydrophobic and electrostatic interactions.

Procedure

The human genome encodes 46 diverse proteins which contain a total of 61 BRDs structurally clustered into eight distinct subfamilies (Figure 2). The first subfamily consists of a functionally diverse group of proteins that includes the HAT P300/CBP-associated factor (PCAF). In fact, it was the solution of the BRD structure of PCAF that proved the ability of BRDs to bind to acetylated lysine’s. The Bromodomain and Extra Terminal (BET) proteins are grouped in the second subfamily and highly specific small molecule inhibitors of this family have recently emerged as promising therapeutic agents in cancer and inflammation. Proteins within the fifth subfamily are structurally characterized by the presence of a methyl-lysine reader domain, the plant homeodomain (PHD) finger in tandem with a BRD. This tandem epigenetic reader module is necessary for the binding to chromatin and highlights a crucial theme in chromatin biology: the multivalent engagement of histone modifications through epigenetic reader proteins that contain more than one reader domain.

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