Coactivator

A coactivator is a type of transcriptional coregulator that binds to an activator (a transcription factor) to increase the rate of transcription of a gene or set of genes. The activator contains a DNA binding domain that binds either to a DNA promoter site or a specific DNA regulatory sequence called an enhancer. Binding of the activator-coactivator complex increases the speed of transcription by recruiting general transcription machinery to the promoter, therefore increasing gene expression. The use of activators and coactivators allows for highly specific expression of certain genes depending on cell type and developmental stage. A coactivator is a type of transcriptional coregulator that binds to an activator (a transcription factor) to increase the rate of transcription of a gene or set of genes. The activator contains a DNA binding domain that binds either to a DNA promoter site or a specific DNA regulatory sequence called an enhancer. Binding of the activator-coactivator complex increases the speed of transcription by recruiting general transcription machinery to the promoter, therefore increasing gene expression. The use of activators and coactivators allows for highly specific expression of certain genes depending on cell type and developmental stage. Some coactivators also have histone acetyltransferase (HAT) activity. HATs form large multiprotein complexes that weaken the association of histones to DNA by acetylating the N-terminal histone tail. This provides more space for the transcription machinery to bind to the promoter, therefore increasing gene expression. Activators are found in all living organisms, but coactivator proteins are typically only found in eukaryotes because they are more complex and require a more intricate mechanism for gene regulation. In eukaryotes, coactivators are usually proteins that are localized in the nucleus. Some coactivators indirectly regulate gene expression by binding to an activator and inducing a conformational change that then allows the activator to bind to the DNA enhancer or promoter sequence. Once the activator-coactivator complex binds to the enhancer, RNA polymerase II and other general transcription machinery are recruited to the DNA and transcription begins. Nuclear DNA is normally wrapped tightly around histones, making it hard or impossible for the transcription machinery to access the DNA. This association is due primarily to the electrostatic attraction between the DNA and histones as the DNA phosphate backbone is negatively charged and histones are rich in lysine residues, which are positively charged. The tight DNA-histone association prevents the transcription of DNA into RNA. Many coactivators have histone acetyltransferase (HAT) activity meaning that they can acetylate specific lysine residues on the N-terminal tails of histones. In this method, an activator binds to an enhancer site and recruits a HAT complex that then acetylates nucleosomal promoter-bound histones by neutralizing the positively charged lysine residues. This charge neutralization causes the histones to have a weaker bond to the negatively charged DNA, which relaxes the chromatin structure, allowing other transcription factors or transcription machinery to bind to the promoter (transcription initiation). Acetylation by HAT complexes may also help keep chromatin open throughout the process of elongation, increasing the speed of transcription. Acetylation of the N-terminal histone tail is one of the most common protein modifications found in eukaryotes, with about 85% of all human proteins being acetylated. Acetylation is crucial for synthesis, stability, function, regulation and localization of proteins and RNA transcripts. HATs function similarly to N-terminal acetyltransferases (NATs) but their acetylation is reversible unlike in NATs. HAT mediated histone acetylation is reversed using histone deactetylase (HDAC), which catalyzes the hydrolysis of lysine residues, removing the acetyl group from the histones. This causes the chromatin to close back up from their relaxed state, making it difficult for the transcription machinery to bind to the promoter, thus repressing gene expression. Examples of coactivators that display HAT activity include CARM1, CBP and EP300.