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J. Biol. Chem., Vol. 281, Issue 28, 19407-19416, July 14, 2006

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Novel FXXFF and FXXMF Motifs in Androgen Receptor Cofactors Mediate High Affinity and Specific Interactions with the Ligand-binding Domain^*

Dennis J. van de Wijngaart, Martin E. van Royen, Remko Hersmus, Ashley C. W. Pike^¶1, Adriaan B. Houtsmuller, Guido Jenster, Jan Trapman, and Hendrikus J. Dubbink²

From the Departments of Urology and Pathology, Josephine Nefkens Institute, Erasmus MC, P. O. Box 1738, 3000 DR Rotterdam, The Netherlands and ^¶Structural Biology Laboratory, Department of Chemistry, University of York, York YO10 5DD, United Kingdom

Upon hormone binding, a hydrophobic coactivator binding groove is induced in the androgen receptor (AR) ligand-binding domain (LBD). This groove serves as high affinity docking site for -helical FXXLF motifs present in the AR N-terminal domain and in AR cofactors. Study of the amino acid requirements at position +4 of the AR FXXLF motif revealed that most amino acid substitutions strongly reduced or completely abrogated AR LBD interaction. Strong interactions were still observed following substitution of Leu+4 by Phe or Met residues. Leu+4 to Met or Phe substitutions in the FXXLF motifs of AR cofactors ARA54 and ARA70 were also compatible with strong AR LBD binding. Like the corresponding FXXLF motifs, interactions of FXXFF and FXXMF variants of AR and ARA54 motifs were AR specific, whereas variants of the less AR-selective ARA70 motif displayed increased AR specificity. A survey of currently known AR-binding proteins revealed the presence of an FXXFF motif in gelsolin and an FXXMF motif in PAK6. In vivo fluorescence resonance energy transfer and functional protein-protein interaction assays showed direct, efficient, and specific interactions of both motifs with AR LBD. Mutation of these motifs abrogated interaction of gelsolin and PAK6 proteins with AR. In conclusion, we have demonstrated strong interaction of FXXFF and FXXMF motifs to the AR coactivator binding groove, thereby mediating specific binding of a subgroup of cofactors to the AR LBD.

Received for publication, March 20, 2006

^* This work was supported by Grant DDHK2001-2402 from the Dutch Cancer Society (KWF). 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: Structural Genomics Consortium, University of Oxford, Botnar Research Centre, Oxford OX3 7LD, UK. Supported by a Wellcome Trust Career Development fellowship (Grant 064803).

² To whom correspondence should be addressed. Tel.: 31-10-4088467; Fax: 31-10-4089487; E-mail: h.dubbink{at}erasmusmc.nl.

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