Binding of the histone chaperone ASF1 to the CBP bromodomain promotes histone acetylation

Abstract

The multifunctional Creb-binding protein (CBP) protein plays a pivotal role in many critical cellular processes. Here we demonstrate that the bromodomain of CBP binds to histone H3 acetylated on lysine 56 (K56Ac) with higher affinity than to its other monoacetylated binding partners. We show that autoacetylation of CBP is critical for the bromodomain-H3 K56Ac interaction, and we propose that this interaction occurs via autoacetylation-induced conformation changes in CBP. Unexpectedly, the bromodomain promotes acetylation of H3 K56 on free histones. The CBP bromodomain also interacts with the histone chaperone anti-silencing function 1 (ASF1) via a nearby but distinct interface. This interaction is necessary for ASF1 to promote acetylation of H3 K56 by CBP, indicating that the ASF1-bromodomain interaction physically delivers the histones to the histone acetyl transferase domain of CBP. A CBP bromodomain mutation manifested in Rubinstein-Taybi syndrome has compromised binding to both H3 K56Ac and ASF1, suggesting that these interactions are important for the normal function of CBP. C hromatin is the physiological template for all genomic processes. The histone proteins that package the DNA into chromatin are subject to posttranslational modifications, including acetylation, methylation, phosphorylation, ubiquitination, and sumoylation, that serve to regulate DNA-templated phenomena such as transcription, replication, repair, and recombination (1). Many histone posttranslational modifications mediate their function by interacting specifically with and recruiting "reader" modules of multifunctional proteins, which often themselves have activities that subsequently further modify the chromatin structure to make the DNA either more or less accessible. For example, the bromodomain is the specific reader module for acetylated lysines on histones and nonhistone proteins (reviewed in ref.2), where acetylation is one of the most abundant posttranslational modifications in human cells.The bromodomain is found in many transcriptional coregulators and histone-modifying complexes, including histone acetyl transferases (HATs), enzymes that themselves mediate acetylation. Structural studies have revealed that bromodomains have a conserved structural fold that consists of a left-handed four-helix bundle and two interspersed ZA and BC loops which constitute the active acetyl lysine-binding pocket (3). Despite this conserved overall structure, different bromodomains recognize distinct acetylated lysines in different proteins because the specific amino acid residues within the loops of each bromodomain are critical for determining the acetyl lysine-binding specificity (4, 5).The general theme for bromodomain function is that they serve to anchor the bromodomain-containing protein to acetylated chromatin templates or to acetylated transcriptional activators. For example, the bromodomains of the yeast ATP-dependent nucleosome remodeler Swi2 and the HAT GCN5 are required for anchoring these chromatin-modifying complexes to acetylated c...

Selective Recognition of H3.1K36 Dimethylation/H4K16 Acetylation Facilitates the Regulation of All-trans-retinoic Acid (ATRA)-responsive Genes by Putative Chromatin Reader ZMYND8

“…example, the CREB-binding protein bromodomain binds to H3K36Ac/H3K56Ac/H4K20Ac (44,45) in a monovalent manner, and bromodomain PHD finger transcription factor/PHD finger binds to H4K16Ac/H3K4Me3 (15) in a multivalent fashion. In our study, ZMYND8 preferentially binds to H3.1K36Me2/Me3 (Fig.…”

The world of protein acetylation

“…p300 is autoacetylated at five lysine positions at the C-terminus resulting in an increased basal activity [201]. The conformational alterations induced by autoacetylation of CBP feature a crucial requirement for H3K53 binding and acetylation [202,203]. In both cases autoacetylation leads to an increased KAT activity.…”

Structural insight into the recognition of acetylated histone H3K56ac mediated by the bromodomain of CREB‐binding protein

“…Further, H3K56ac has been found in mammals at a significant but low abundance of 1%. Most importantly, this recognition promotes histone acetyltransferase (HAT)-dependent acetylation of H3K56 on free histones, which is proposed to be delivered to replication-dependent chaperones for chromatin assembly [19]. Accordingly, human histone deacetylases, e.g., sirtuin (SIRT) 1, SIRT3 and SIRT6, deacetylate H3K56 on both free histones and reconstituted mononucleosomes in vitro [14,18].…”