Activation function 2 in the human androgen receptor ligand binding domain mediates interdomain communication with the NH(2)-terminal domain.
Activation function 2 in the ligand binding domain of nuclear receptors forms a hydrophobic cleft that binds the LXXLL motif of p160 transcriptional coactivators. Here we provide evidence that activation function 2 in the androgen receptor serves as the contact site for the androgen dependent NH(2)- and carboxyl-terminal interaction of the androgen receptor and only weakly interacts with p160 coactivators in an LXXLL-dependent manner. Mutagenesis studies indicate that it is the NH(2)-/carboxyl-terminal interaction that is required by activation function 2 to stabilize helix 12 and slow androgen dissociation critical for androgen receptor activity in vivo. The androgen receptor recruits p160 coactivators through its NH(2)-terminal and DNA binding domains in an LXXLL motif-independent manner. The results suggest a novel function for activation function 2 and a unique mechanism of nuclear receptor transactivation.
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Laboratories for Reproductive Biology, Department of Pediatrics, University of North Carolina, Chapel Hill, North Carolina 27599-7500, USA.
Kemppainen
J A
JA
Voegel
J J
JJ
Gronemeyer
H
H
Wilson
E M
EM
D020816:Amino Acid Motifs; D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D006801:Humans; D017433:Protein Structure, Secondary; D011944:Receptors, Androgen / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship; D015533:Transcriptional Activation
D011944:Receptors, Androgen