Anything but simple: a phosphorylation-driven toggle within Brd4 triggers gene-specific transcriptional activation

Abstract

In this issue of Molecular Cell, Wu et al. (2013) report their extraordinary findings on the molecular mechanism that controls gene-specific targeting by Brd4, a universal epigenetic reader.

Figure 1.. CK2-Mediated Phosphorylation Triggers Structural Reorganization within Brd4 that Facilitates Productive Binding to Acetylated Chromatin and p53

(A) Domain organization of human Brd4 protein. Domains of Brd4 are indicated as colored rectangles with amino acid indicated above their respective boxes. They include bromodomain 1 (BD1), phosphorylation-dependent interaction domain (PDID, dotted-line rectangle) spanning bromodomain 2 (BD2) and the N-terminal cluster of phosphorylation sites (NPS), the basic residue-enriched interaction domain (BID), extra-terminal domain (ET), and C-terminal motif (CTM). (B) Model. In its dephosphorylated state, Brd4 interacts with p53 exclusively via BID while the NPS makes intramolecular contacts with BD2 (shown as black dotted lines). As a result, Brd4 association with acetylated chromatin is blocked and transcription of the p53-controlled gene is off. CK2 phosphorylates serine residues within NPS, which drives its association with the positively charged BID domain (shown as red dots). That liberates BD2 and promotes cooperative binding of the individual BDs within Brd4 to acetylated chromatin. p53 in this setting binds exclusively to hyperphosphorylated PDID and brings Brd4 to the promoters of p53-controlled genes, leading to promoter-specific activation of transcription.