1. Academic Validation
  2. The molecular mechanisms of coactivator utilization in ligand-dependent transactivation by the androgen receptor

The molecular mechanisms of coactivator utilization in ligand-dependent transactivation by the androgen receptor

  • J Biol Chem. 2005 Mar 4;280(9):8060-8. doi: 10.1074/jbc.M407046200.
Eva Estébanez-Perpiñá 1 Jamie M R Moore Ellena Mar Edson Delgado-Rodrigues Phuong Nguyen John D Baxter Benjamin M Buehrer Paul Webb Robert J Fletterick R Kiplin Guy
Affiliations

Affiliation

  • 1 Department of Biochemistry and Biophysics, University of California, San Francisco, California 94143, USA.
Abstract

Androgens drive sex differentiation, bone and muscle development, and promote growth of hormone-dependent cancers by binding the nuclear Androgen Receptor (AR), which recruits coactivators to responsive genes. Most nuclear receptors recruit steroid receptor coactivators (SRCs) to their ligand binding domain (LBD) using a leucine-rich motif (LXXLL). AR is believed to recruit unique coactivators to its LBD using an aromatic-rich motif (FXXLF) while recruiting SRCs to its N-terminal domain (NTD) through an alternate mechanism. Here, we report that the AR-LBD interacts with both FXXLF motifs and a subset of LXXLL motifs and that contacts with these LXXLL motifs are both necessary and sufficient for SRC-mediated AR regulation of transcription. Crystal structures of the activated AR in complex with both recruitment motifs reveal that side chains unique to the AR-LBD rearrange to bind either the bulky FXXLF motifs or the more compact LXXLL motifs and that AR utilizes subsidiary contacts with LXXLL flanking sequences to discriminate between LXXLL motifs.

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