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

Eva Estébanez-Perpiñá, 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

Research output: Contribution to journalArticle

122 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)8060-8068
Number of pages9
JournalJournal of Biological Chemistry
Volume280
Issue number9
DOIs
StatePublished - Mar 4 2005

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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