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J. Biol. Chem., Vol. 281, Issue 10, 6648-6663, March 10, 2006

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Probing the Functional Link between Androgen Receptor Coactivator and Ligand-binding Sites in Prostate Cancer and Androgen Insensitivity^*

Bin He¹, Robert T. Gampe, Jr., Andrew T. Hnat, Jonathan L. Faggart, John T. Minges, Frank S. French, and Elizabeth M. Wilson²

From the Laboratories for Reproductive Biology, Lineberger Comprehensive Cancer Center, Department of Pediatrics, Biochemistry and Biophysics, University of North Carolina, Chapel Hill, North Carolina 27599 and Discovery Research, GlaxoSmithKline, Research Triangle Park, North Carolina 27709

The androgen receptor (AR) is a ligand-activated transcription factor required for male sex development and virilization and contributes to prostate cancer initiation and progression. High affinity androgen binding triggers conformational changes required for AR transactivation. Here we characterized naturally occurring AR gene mutations in the region of activation function 2 (AF2) that decrease or increase AR transcriptional activity by altering the region bounded by AF2 and the ligand binding pocket without affecting equilibrium androgen binding affinity. In the androgen insensitivity syndrome, germ line AR mutations increase the androgen dissociation rate and reduce AR FXXLF motif binding and the recruitment of steroid receptor coactivator (SRC)/p160 coactivator LXXLL motifs. In prostate cancer, somatic AR mutations in AF2 or near the bound ligand slow androgen dissociation and increase AR stabilization and coactivator recruitment. Crystal structures of the AR ligand binding domain bound to R1881 and FXXLF or LXXLL motif peptide indicate the mutations are proximal to the AF2 bound peptide, adjacent to the ligand pocket, or in a putative ligand gateway. The results suggest a bidirectional structural relay between bound ligand and coactivator that establishes AR functional potency in vivo.

Received for publication, October 31, 2005 , and in revised form, December 16, 2005.

^* This work was supported by United States Public Health Service Grant HD16910 from the NICHD, by cooperative agreement U54-HD35041 as part of the Specialized Cooperative Centers Program in Reproductive Research of the National Institutes of Health, and by Fogarty International Center Grant R03TW001234 (to B. H.) Training and Research in Population and Health (to F. S. F.) by the National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Present address: M533 DeBakey Bldg., Dept. of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030

² To whom correspondence should be addressed: Laboratories for Reproductive Biology, CB 7500, University of North Carolina, Chapel Hill NC 27599-7500. Tel.: 919-966-5168; Fax: 919-966-2203; E-mail: emw{at}med.unc.edu.

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