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Bromodomain (PCAF)

Introduction

The bromodomain is an evolutionary conserved motif found in chromatin remodeling complexes. It has been identified in over 100 proteins from multiple organisms ranging from unicellular microscopic eukaryotes (e.g., yeast) to humans. The motif is best known for the groundbreaking recent discoveries made to identify it as the only acetyl-lysine binding domain^[1] and to reveal its highly specific ligand selectivity properties^[2]. Due to these novel characteristics, bromodomains are typically found in proteins responsible for modifications in chromatin structure and the regulation of gene expression, such as histone acetyltransferases (HATs), and the ATPase subunits of chromatin remodeling complexes. There are several families of proteins with bromodomains. One such family is the human transcriptional coactivator p300/CBP-associated factor (PCAF) bromodomain.

Structure and Function

Structure

The bromodomain was originally identified as a sequence of roughly 60 amino acid residues that forms 2 alpha helices^[3]. However, it is now known that the bromodomain consist of a highly conserved sequence of approximately 110 amino acids^[4]. The structure of the PCAF bromodomain consists of a bundle (alphaZ, aA,aB, and aC) with a left-handed twist, and a long intervening loop between helices Z and A (ZA loop)^[1]. The ZA loop of the bromodomain has a defined conformation and is packed against the loop between helices aB and aC (BC loop) to form a hydrophobic pocket. This pocket created by the ZA and BC loops is lined by specific residues (Val 752, Ala 757, Tyr 760, Val 763, Tyr 802 and Tyr 809) that support protein-protein interactions. The ZA loop varies in length between different bromodomains, but almost always contains residues corresponding to Phe 748, Pro 751, Pro 758, Tyr 760 and Pro 767^[1].

Function

Until recently, the function of the bromodomain remained unknown. Its structure and modularity, along with its feature of both N and C termini located together on one end of the protein, suggested that it played a role in protein-protein interactions. It has now been shown that the hydrophobic pocket formed by the loops is the primary binding site for acetyl-lysine proteins, making the bromodomain a functional site for recognition of acetylated lysine residues playing a role in regulation via protein-protein interactions^[1]. This interaction has been shown via localization and chemical shift experiments that revealed the specific manner with which the bromodomain hydrophobic cavity binds to acetylated lysine residues.

Once the acetyl-lysine residue makes the initial binding inside the hydrophobic pocket, the ZA and BC loop residues at the entrance of the pocket interact with the amino acids adjacent (+/- 1 or 2) to the already bound acetyl-lysine. Those interactions reinforce binding of the target sequence^[5].

It is also believed that the bromodomain may also play a role in highly specific histone acetylation by tethering transcriptional HATs to specific chromosomal sites^[6]