Structure and ligand of a histone acetyltransferase bromodomain

Abstract

Histone acetylation is important in chromatin remodelling and gene activation. Nearly all known histone-acetyltransferase (HAT)-associated transcriptional co-activators contain bromodomains, which are approximately 110-amino-acid modules found in many chromatin-associated proteins. Despite the 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 factor). The structure reveals an unusual left-handed up-and-down four-helix bundle. In addition, we show by a combination of structural and site-directed mutagenesis studies that bromodomains can interact specifically with acetylated lysine, making them the first known protein modules to do so. The nature of the recognition of acetyl-lysine by the P/CAF bromodomain is similar to that of acetyl-CoA by histone acetyltransferase. Thus, the bromodomain is functionally linked to the HAT activity of co-activators in the regulation of gene transcription.

PWWP domains and their modes of sensing DNA and histone methylated lysines

“…Finally, histone PTMs may work as specific docking sites for protein readers that selectively bind to chromatin and direct downstream events (Turner et al 1992;Ruthenburg et al 2011). The identification of the bromodomain as an acetyl-lysine reader module further confirmed this idea and suggested the existence of other effector proteins capable of reading histone PTMs (Dhalluin et al 1999). …”

Coactivators and general transcription factors have two distinct dynamic populations dependent on transcription

“…Several SAGA and ATAC subunits have “reader” domains that interact directly with chromatin by recognizing specific transcription‐associated histone modifications. For example, GCN5 (or PCAF) has a bromodomain that binds preferentially to acetylated H3 and H4 histone tail peptides (Dhalluin et al , 1999; Hudson et al , 2000), while SGF29 contains tandem tudor domains, which was shown to bind H3K4me3 (Vermeulen et al , 2010; Bian et al , 2011). …”

Deficient Histone Acetylation in Acute Leukemia and the Correction by an Isothiocyanate

“…Among the many post-translational modifications of histones is histone acetylation, which plays a key role in the regulation of transcription by modulating chromatin structure [1,2,3,4]. Acetylated lysines of histones provide interaction with specific effector modules such as bromodomain complexes which may mediate transcriptional regulation [5]. The Polycomb protein shares a homologous domain with a heterochromatin-associated protein of Drosophila [6].…”