Structure and ligand of a histone acetyltransferase bromodomain

Histone acetylation is important in chromatin remodelling and gene activati on(1-4). Nearly all known histone-acetyltransferase (HAT)-associated transc riptional co-activators contain bromodomains, which are similar to 110-amin o-acid modules found in many chromatin-associated proteins(5-9). Despite th e wide occurrence of these bromodomains, their three-dimensional structure and binding partners remain unknown. Here we report the solution structure of the bromodomain of the HAT co-activator P/CAF (p300/CBP-associated facto r)(10,11). The structure reveals an unusual left-handed up-and-down four-he lix bundle. In addition, we show by a combination of structural and site-di rected mutagenesis studies that bromodomains can interact specifically with acetylated lysine, making them the first known protein modules to do so, T he nature of the recognition of acetyl-lysine by the P/CAF bromodomain is s imilar to that of acetyl-CoA by histone acetyltransferase. Thus, the bromod omain is functionally linked to the HAT activity of co-activators in the re gulation of gene transcription.