Nuclear receptor coactivators: structural and functional biochemistry

Abstract

Transcription of eukaryotic cell is a multistep process tightly controlled by concerted action of macromolecules. Nuclear receptors are ligand-activated sequence-specific transcription factors that bind DNA and activate (or repress) transcription of specific sets of nuclear target genes. Successful activation of transcription by nuclear receptors and most other transcription factors requires "coregulators" of transcription. Coregulators make up a diverse family of proteins that physically interact with and modulate the activity of transcription factors and other components of the gene expression machinery via multiple biochemical mechanisms. The coregulators include coactivators that accomplish reactions required for activation of transcription and corepressors that suppress transcription. This review summarizes our current knowledge of nuclear receptor coactivators with an emphasis on their biochemical mechanisms of action and means of regulation.

Figure 1

Multiple activities of NR coactivators are coordinated for transcriptional activation. Abbreviations: NR, nuclear receptor; NRE, NR-responsive element; TSS, transcription start site; P, phosphorylation; Me, methylation; Ac, acetylation; GTFs, general transcription factors; CoAct, coactivator; RRM, RNA recognition motif (also see the text). NR binding to NRE is followed by sequential recruitment and action of coactivator complexes with specialized activities. PTM enzymes (HMT, kinases, and KAT) prepare chromatin for transcription by marking histones, while looping CoActs bring the promoter and enhancer together. Chromatin marks are recognized by coactivating chromatin “readers” (e.g., via chromo and bromo domains) and cause recruitment of chromatin remodelers (SWI/SNF). This allows for stable binding of polII and GTFs for transcription initiation and elongation with the help of elongation coactivators (e.g., MEDIATOR). CoActs also take part in subsequent steps, including mRNA splicing, export, and translation. The consecutive replacement of coactivator complexes is tightly controlled by proteasomal turnover.

Figure 2

Diverse actions of coactivator SRC-3 are dictated by specific PTMs. Dependent on the site and identity of PTM, SRC-3 can participate in different biological processes, such as signaling adaptor, translationar repressor, splicing coactivator, or transcription initiation together with other coactivators. Abbreviations: P, phosphorylation; Ac, acetylation; Me, methylation. Different positions of phosphorylation indicate different phosphorylation sites on the coactivator molecule.