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J. Biol. Chem., Vol. 276, Issue 45, 42293-42301, November 9, 2001
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From the Laboratories for Reproductive Biology, the Departments of
Biochemistry and Biophysics, and the Department of Pediatrics,
University of North Carolina, Chapel Hill, North Carolina 27599
The androgen receptor
undergoes an androgen-specific NH2- and COOH-terminal
interaction between NH2-terminal motif FXXLF
and activation function 2 in the ligand binding domain. We demonstrated previously that activation function 2 forms overlapping binding sites
for the androgen receptor FXXLF motif and the
LXXLL motifs of p160 coactivators. Here we investigate the
influence of the NH2- and COOH-terminal interaction on
androgen receptor function. Specificity and relative potency of the
motif interactions were evaluated by ligand dissociation rate and the
stability of chimeras of transcriptional intermediary factor 2 with
full-length and truncated androgen or glucocorticoid receptor. The
results indicate that the androgen receptor activation function 2 interacts specifically and with greater avidity with the single
FXXLF motif than with the LXXLL motif region of
p160 coactivators, whereas this region of the glucocorticoid receptor
interacts preferentially with the LXXLL motifs. Expression
of the LXXLL motifs as a fusion protein with the
glucocorticoid receptor resulted in loss of agonist-induced receptor
destabilization and increased half-time of ligand dissociation. The
NH2- and COOH-terminal interaction inhibited binding and
activation by transcriptional intermediary factor 2. We conclude that
the androgen receptor NH2- and COOH-terminal interaction
reduces the dissociation rate of bound androgen, stabilizes the
receptor, and inhibits p160 coactivator recruitment by activation
function 2.
Androgen-induced NH2- and COOH-terminal Interaction
Inhibits p160 Coactivator Recruitment by Activation Function 2*
*
This work was supported by NICHD, National Institutes of
Health (NIH) Public Health Service Grant HD16910, by cooperative agreement U54-HD35041 as part of the Specialized Cooperative Centers Program in Reproductive Research of National Institutes of Health, and
by the International Training and Research in Population and Health
Program supported by the Fogarty International Center and NICHD, NIH.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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