Localization of functional domains in the androgen receptor

Abstract

Functional domains of the androgen receptor (AR) have been localized through a combination of studies on naturally occurring AR gene mutations, in vitro mutagenesis studies and comparison with the structure of other members of the steroid/nuclear receptor superfamily. Two activation domains exist within the amino-terminal domain, and a ligand-dependent activation domain is present in the ligand binding domain. The poly(Gln) stretch within the amino-terminal domain may inhibit the transactivation function of the receptor. Different ligands or binding to different promoters may recruit the use of different activation domains, which may provide promoter-specific effects of receptor action. Co-activator proteins that modulate or enhance AR action have been identified, many of which interact with the ligand binding domain of the AR. Tissue-specific expression of such co-activators, and promoter-specific protein interactions, may also help control the specificity of androgen action. Target Ser residues for phosphorylation have been identified, which may be the site of action for cross-talk from protein kinase signalling pathways. However, the role of phosphorylation in AR function in general is still unclear. It is now clear that interactions occur between receptor domains, modulating functions including ligand dissociation, dimerization and transactivation. By studying the functional domains of the AR, and how they control receptor function in response to different activation signals, we are beginning to understand the mechanisms controlling the specificity of receptor action.