Identification of SRC3/AIB1 as a preferred coactivator for hormone-activated androgen receptor.
Transcription activation by androgen receptor (AR), which depends on recruitment of coactivators, is required for the initiation and progression of prostate cancer, yet the mechanisms of how hormone-activated AR interacts with coactivators remain unclear. This is because AR, unlike any other nuclear receptor, prefers its own N-terminal FXXLF motif to the canonical LXXLL motifs of coactivators. Through biochemical and crystallographic studies, we identify that steroid receptor coactivator-3 (SRC3) (also named as amplified in breast cancer-1 or AIB1) interacts strongly with AR via synergistic binding of its first and third LXXLL motifs. Mutagenesis and functional studies confirm that SRC3 is a preferred coactivator for hormone-activated AR. Importantly, AR mutations found in prostate cancer patients correlate with their binding potency to SRC3, corroborating with the emerging role of SRC3 as a prostate cancer oncogene. These results provide a molecular mechanism for the selective utilization of SRC3 by hormone-activated AR, and they link the functional relationship between AR and SRC3 to the development and growth of prostate cancer.
Zhou
X Edward
XE
Laboratory of Structural Sciences, Van Andel Research Institute, Grand Rapids, Michigan 49503, USA.
Suino-Powell
Kelly M
KM
Li
Jun
J
He
Yuanzheng
Y
Mackeigan
Jeffrey P
JP
Melcher
Karsten
K
Yong
Eu-Leong
EL
Xu
H Eric
HE
D020816:Amino Acid Motifs; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D018360:Crystallography, X-Ray / Q000379:methods; D005786:Gene Expression Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D016296:Mutagenesis; D009154:Mutation; D056921:Nuclear Receptor Coactivator 3 / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011944:Receptors, Androgen / Q000378:metabolism*
D011944:Receptors, Androgen; D056921:Nuclear Receptor Coactivator 3