Abstract
Backgroundp300/CBP associating factor (PCAF, also known as KAT2B for lysine acetyltransferase 2B) is a catalytic subunit of megadalton metazoan complex ATAC (Ada-Two-A containing complex) for acetylation of histones. However, relatively little is known about the regulation of the enzymatic activity of PCAF.ResultsHere we present two dimeric structures of the PCAF acetyltransferase (HAT) domain. These dimerizations are mediated by either four-helical hydrophobic interactions or a ß-sheet extension. Our chemical cross-linking experiments in combined with site-directed mutagenesis demonstrated that the PCAF HAT domain mainly forms a dimer in solution through one of the observed interfaces. The results of maltose binding protein (MBP)-pulldown, co-immunoprecipitation and multiangle static light scattering experiments further indicated that PCAF dimeric state is detectable and may possibly exist in vivo.ConclusionsTaken together, our structural and biochemical studies indicate that PCAF appears to be a dimer in its functional ATAC complex.
Highlights
The unique posttranslational modification patterns on histones have been conceptualized as epigenetic codes that may finely tune transcription of specific genes [1,2]
We found four Histone acetyltransferase (HAT) domains in one asymmetric unit (Additional file 1: Figure 1S)
Since PCAF/General control nonderepressible 5 (GCN5) always exist in megadalton complexes, one possibility is that PCAF dimerization may help to better associate with a nucleosome for efficient histone acetylation, which is depicted in our proposed model (Figure 5)
Summary
The unique posttranslational modification patterns on histones have been conceptualized as epigenetic codes that may finely tune transcription of specific genes [1,2]. Histone acetyltransferases (HATs), including p300/CBP and PCAF/GCN5, are responsible for modification of histones by acetylation on the exposed lysines [3,4,5]. PCAF/GCN5 are important members of histone acetyltransferases. Homozygous GCN5 knockout mice died during embryogenesis, while the majority of PCAF knockout mice developed normal [6,7]. The PCAF knockout mice later showed memory impairment, psychological anxiety and defects in stress control [8,9]. A single nucleotide polymorphism in the PCAF gene was found in patients with coronary heart abnormalities that resulted in vascular morbidity and mortality [10]
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