Structural Basis for Androgen Receptor Interdomain and Coactivator Interactions Suggests a Transition in Nuclear Receptor Activation Function Dominance
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Abstract
The androgen receptor (AR) is required for male sex development and contributes to
prostate cancer cell survival. In contrast to other nuclear receptors that bind the
LXXLL motifs of coactivators, the AR ligand binding domain is preferentially engaged
in an interdomain interaction with the AR FXXLF motif. Reported here are crystal structures
of the ligand-activated AR ligand binding domain with and without bound FXXLF and
LXXLL peptides. Key residues that establish motif binding specificity are identified
through comparative structure-function and mutagenesis studies. A mechanism in prostate
cancer is suggested by a functional AR mutation at a specificity-determining residue
that recovers coactivator LXXLL motif binding. An activation function transition hypothesis
is proposed in which an evolutionary decline in LXXLL motif binding parallels expansion
and functional dominance of the NH(2)-terminal transactivation domain in the steroid
receptor subfamily.