Download MendeleyIdentification of SRC3/AIB1 as a Preferred Coactivator for Hormone-activated Androgen Receptor.
Zhou, X.E., Suino-Powell, K.M., Li, J., He, Y., Mackeigan, J.P., Melcher, K., Yong, E.L., Xu, H.E.(2010) J Biol Chem 285: 9161-9171
- PubMed: 20086010
- DOI: https://doi.org/10.1074/jbc.M109.085779
- Primary Citation of Related Structures:
3L3X, 3L3Z - PubMed 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.
Organizational Affiliation:
Laboratory of Structural Sciences, Van Andel Research Institute, Grand Rapids, Michigan 49503, USA.
