4N3W is a 2-domain of a bromodomain (BrD) and a plant homeodomain (PHD) that functions in humans to recognize the epigenetic acetylation of histones. It is a portion of the larger complex of human transcriptional co-activator CREB-binding protein (CBP).
Function
Bromodomains (BrDs) function exclusively as acetyl-lysine binding domains to regulate gene transcription in both histone and non-histone proteins[1]. This BrD of human transcriptional co-activator CBP binds with relatively high specificity to Lys20-acetylated histone H4 (H4K20), though this preference is not well-understood. The plant homeodomain (PHD) finger is hypothesized to play a structural role, since the entire module functions as one unit. It has been experimentally demonstrated that the module binds most effectively to singly acetylated peptide chains, with affinity significantly reduced with more acetylations. This is a somewhat unique feature, as most BrDs have shown preference to diacetylated histone peptides[2]. It has also been shown that the bromodomain, along with a preferential affinity for single acetylations, it also prefers lysine-acetylated motifs comprising a hydrophobic or aromatic residue at -2 and a lysine or arginine at the -3 or -4 position[3] from the acetylated lysine.
Disease
In the larger complex, this domain functions as the domain that binds directly to the histone protein when it recognizes acetylation. Alterations in the of the human CBP gene results have been implicated in hematological malignancies as well as congenital malformation and mental retardation[4].
Relevance
Bromodomains have become a popular target for their role in human disease since they recognize the acetylation epigenetic tag. Potential drug targets for BrDs include inhibitors to aid in rheumatoid arthritis[5], and certain types of cancer like squamous carcinoma[6].
Structural highlights
This protein is composed of two different domains -- the bromodomain (BrD) and the plant homeodomain (PHD) finger. In this particular module for human CBP, the two come together to form such interactions that they function as a single structural unit.There are two that serve as a stable base for an extended interface established between the PHD finger and the BrD. The PHD finger itself has not shown to bind any specific peptide, whether in tandem or in its individual construct [7]. The separation of the domains is shown , with the BrD shown in aquamarine, the PHD finger shown in red, and the linkers of the two domains shown in blue.
There are two different sections which are missing electron density in their region, which suggests a high degree of structural mobility in solution. These regions are from and . Though unshown in the crystal structure, the lack of electron density associated with such a lack of imaging suggests a high degree of structural mobility through these sections.
In the in the BrD (shown here as the space between the 4 crimson helices), 5 water molecules are stably bound within. This pocket is in proximity to the region where the histone peptide actually binds, which is shown , with the red stick-and-wireframe showing the histone peptide.
