title: Analysis of interdomain interactions of the androgen receptor.
abstract: High-affinity binding of testosterone or dihydrotestosterone to the androgen receptor (AR) triggers the androgen-dependent AR NH2- and carboxyl-terminal (N/C) interaction between the AR NH2-terminal FXXLF motif and the activation function 2 (AF2) hydrophobic binding surface in the ligand-binding domain. The functional importance of the AR N/C interaction is supported by naturally occurring loss-of-function AR AF2 mutations where AR retains high-affinity androgen binding but is defective in AR FXXLF motif binding. Ligands with agonist activity in vivo such as testosterone, dihydrotestosterone, and the synthetic anabolic steroids induce the AR N/C interaction and increase AR transcriptional activity in part by slowing the dissociation rate of bound ligand and stabilizing AR against degradation. AR ligand-binding domain competitive antagonists inhibit the agonist-dependent AR N/C interaction. Although the human AR N/C interaction is important for transcriptional activity, it has an inhibitory effect on transcriptional activity from AF2 by competing for p160 coactivator LXXLL motif binding. The primate-specific AR coregulatory protein, melanoma antigen gene protein-A11 (MAGE-A11), modulates the AR N/C interaction through a direct interaction with the AR FXXLF motif. Inhibition of AF2 transcriptional activity by the AR N/C interaction is relieved by AR FXXLF motif binding to the F-box region of MAGE-11. Described here are methods to measure the androgen-dependent AR N/C interdomain interaction and the influence of transcriptional coregulators.
authors.affiliation: Laboratories for Reproductive Biology, Lineberger Comprehensive Cancer Center, Department of Pediatrics, University of North Carolina, Chapel Hill, NC 27599, USA. emw@med.unc.edu
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Wilson
mesh_terms: D045744:Cell Line, Tumor; D005822:Genetic Vectors / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D008297:Male; D054730:Protein Interaction Domains and Motifs; D011944:Receptors, Androgen / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D012107:Research Design; D014162:Transfection; D020798:Two-Hybrid System Techniques
chemical_list: D011944:Receptors, Androgen