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Papers In Press, published online ahead of print May 11, 2006
Pathology, Josephine Nefkens Institute/Room BE330A, Rotterdam 3000 DR
Corresponding Author: h.dubbink{at}erasmusmc.nl
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 a-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 L+4 by F or M residues. L+4 to M or F substitutions in the FxxLF motifs of AR cofactors ARA54 and ARA70 were also compatible with strong AR LBD binding. Like the corresponding FxxLF motifs, interaction 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 (FRET) 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 demonstrate 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.
J. Biol. Chem, 10.1074/jbc.M602567200
Submitted on March 20, 2006
Accepted on May 11, 2006
Novel FxxFF and FxxMF motifs in androgen receptor cofactors mediate high affinity and specific interactions with the ligand-binding domain
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