title: Identification of SRC3/AIB1 as a preferred coactivator for hormone-activated androgen receptor.
abstract: 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.
authors.affiliation: Laboratory of Structural Sciences, Van Andel Research Institute, Grand Rapids, Michigan 49503, USA.
authors.forename: X Edward
authors.initials: XE
authors.lastname: Zhou
authors.forename: Kelly M
authors.initials: KM
authors.lastname: Suino-Powell
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.forename: Yuanzheng
authors.initials: Y
authors.lastname: He
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: Mackeigan
authors.forename: Karsten
authors.initials: K
authors.lastname: Melcher
authors.forename: Eu-Leong
authors.initials: EL
authors.lastname: Yong
authors.forename: H Eric
authors.initials: HE
authors.lastname: Xu
mesh_terms: 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*
chemical_list: D011944:Receptors, Androgen; D056921:Nuclear Receptor Coactivator 3