Allosteric Activation of p300 Autoacetylation by the Tumor Suppressor p53

The transcriptional coactivator p300 (KAT3B) is an essential protein with an intrinsic lysine acetyltransferase activity. As a coactivator, p300 is essential for p53 transactivation; however, its precise role in p53 transactivation remains unclear. Here, we report that in addition to being a substrate, p53 allosterically activates the acetyltransferase activity of p300. Mechanistically, the activation occurs through the enhancement of p300 autoacetylation. Cryo-electron microscopic analysis of the p53-p300 complex revealed that the domain organization of p300 is substantially altered upon binding of p53, suggesting a p53-induced "conformational switch" in the p300 structure, between an inactive and a catalytically active form. Analysis of the genome-wide occupancy of autoacetylated p300 after p53-mediated activation revealed enrichment of acetylated p300 near the transcription start sites of many p53-regulated genes. This is accompanied by a similar enrichment of activating histone marks near those sites. We conclude that allosteric activation of p300 by p53 allows p300 to be hyperactive only near the region of p53 regulated genes, thus, imparting an additional layer of specificity enhancement mechanism in the regulation of gene expression. Such a mechanism could be an important component of imparting locale-specific alteration of other epigenetic marks.