Structural basis for androgen receptor interdomain and coactivator interactions suggests a transition in nuclear receptor activation function dominance.
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.
He
Bin
B
Laboratories for Reproductive Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Gampe
Robert T
RT
Kole
Adam J
AJ
Hnat
Andrew T
AT
Stanley
Thomas B
TB
An
Gang
G
Stewart
Eugene L
EL
Kalman
Rebecca I
RI
Minges
John T
JT
Wilson
Elizabeth M
EM
D020816:Amino Acid Motifs; D001665:Binding Sites; D006801:Humans; D008024:Ligands; D008297:Male; D016296:Mutagenesis; D009154:Mutation / Q000235:genetics*; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D051958:Nuclear Receptor Coactivator 2; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism; D025941:Protein Interaction Mapping; D011944:Receptors, Androgen / Q000737:chemistry* / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation
D008024:Ligands; D009687:Nuclear Proteins; D051958:Nuclear Receptor Coactivator 2; D010446:Peptide Fragments; D011944:Receptors, Androgen; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors