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Domain Interactions between Coregulator ARA₇₀ and the Androgen Receptor (AR)

Departments of Pediatrics (Z-X.Z., S.H.H., E.M.W., F.S.F.) and Biochemistry and Biophysics (B.H., E.M.W.), and The Laboratories for Reproductive Biology, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599-7500

Address all correspondence and requests for reprints to: Dr. Frank S. French, Department of Pediatrics, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599-7500. E-mail: fsfrench{at}med.unc.edu

The coregulator function of AR-associated protein 70 (ARA₇₀) was investigated to further characterize its interaction with the AR. Using a yeast two-hybrid assay, androgen-dependent binding of ARA₇₀ deletion mutants to the AR ligand-binding domain (LBD) was strongest with ARA₇₀ amino acids 321–441 of the 614 amino acid ARA₇₀ protein. Mutations adjacent to or within an FxxLF motif in this 120-amino acid region abolished androgen-dependent binding to the AR-LBD both in yeast and in glutathione-S-transferase affinity matrix assays. Yeast one-hybrid assays revealed an intrinsic ARA₇₀ transcriptional activation domain within amino acids 296–441. In yeast assays the ARA₇₀ domains for transcriptional activation and for binding to the AR-LBD were inhibited by the C-terminal region of ARA₇₀. Full-length ARA₇₀ increased androgen-dependent AR transactivation in transient cotransfection assays using a mouse mammary tumor virus-luciferase reporter in CV1 cells. ARA₇₀ also increased constitutive transcriptional activity of an AR NH₂-terminal-DNA binding domain fragment and bound this region in glutathione-S-transferase affinity matrix assays. Binding was independent of the ARA₇₀ FxxLF motif. The results identify an ARA₇₀ motif required for androgen-dependent interaction with the AR-LBD and demonstrate that ARA₇₀ can interact with the NH₂-terminal and carboxyl-terminal regions of AR.

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