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J. Biol. Chem., Vol. 277, Issue 12, 10226-10235, March 22, 2002
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From the Laboratories for Reproductive Biology and the Departments
of Biochemistry and Biophysics, and Pediatrics, University of North
Carolina, Chapel Hill, North Carolina 27599
The androgen receptor (AR) activation function 2 region of the ligand binding domain binds the LXXLL motifs
of p160 coactivators weakly, engaging instead in an
androgen-dependent, interdomain interaction with an
FXXLF motif in the AR NH2 terminus. Here we show that FXXLF motifs are present in previously reported
AR coactivators ARA70/RFG, ARA55/Hic-5, and ARA54, which account for
their selection in yeast two-hybrid screens. Mammalian two-hybrid
assays, ligand dissociation rate studies, and glutathione
S-transferase adsorption assays indicate
androgen-dependent selective interactions of these FXXLF motifs with the AR ligand binding domain. Mutagenesis
of residues within activation function 2 indicates distinct but
overlapping binding sites where specificity depends on sequences within
and flanking the FXXLF motif. Mutagenesis of the
FXXLF motifs eliminated interaction with the ligand binding
domain but only modestly reduced AR coactivation in transcription
assays. The studies indicate that the FXXLF binding motif
is specific for the AR and mediates interactions both within the AR and
with coregulatory proteins.
The FXXLF Motif Mediates Androgen Receptor-specific
Interactions with Coregulators*
*
This work was supported by Public Health Service Grant
HD16910 from the NICHD, National Institutes of Health, by Cooperative Agreement U54-HD35041 as part of the Specialized Cooperative Centers Program in Reproductive Research of National Institutes of Health, by
United States Army Medical Research and Material Command Grant DAMD17-00-1-0094, and by the International Training and Research in
Population and Health Program supported by the Fogarty International Center and NICHD, National Institutes of Health.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: CB 7500, Rm. 374, Medical Sciences Research Bldg., University of North Carolina, Chapel
Hill, NC 27599. Tel.: 919-966-5168; Fax: 919-966-2203; E-mail:
emw@med.unc.edu.
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