The structural basis of androgen receptor activation: Intramolecular and intermolecular amino-carboxy interactions

Fred Schaufele, Xavier Carbonell, Martin Guerbadot, Sabine Borngraeber, Mark S. Chapman, Aye Aye K Ma, Jeffrey N. Miner, Marc I. Diamond

Research output: Contribution to journalArticlepeer-review

154 Scopus citations

Abstract

Nuclear receptors (NRs) are ligand-regulated transcription factors important in human physiology and disease. In certain NRs, including the androgen receptor (AR), ligand binding to the carboxyterminal domain (LBD) regulates transcriptional activation functions in the LBD and amino-terminal domain (NTD). The basis for NTD-LBD communication is unknown but may involve NTD-LBD interactions either within a single receptor or between different members of an AR dimer. Here, measurement of FRET between fluorophores attached to the NTD and LBD of the AR established that agonist binding initiated an intramolecular NTD-LBD interaction in the nucleus and cytoplasm. This intramolecular folding was followed by AR self-association, which occurred preferentially in the nucleus. Rapid, ligand-induced intramolecular folding and delayed association also were observed for estrogen receptor-α but not for peroxisome proliferator activated receptor-γ2. An antagonist ligand, hydroxyflutamide, blocked the NTD-LBD association within AR. NTD-LBD association also closely correlated with the transcriptional activation by heterologous ligands of AR mutants isolated from hormone-refractory prostate tumors. Intramolecular folding, but not AR-AR affinity, was disrupted by mutation of an α-helical (23FQNLF27) motif in the AR NTD previously described to interact with the AR LBD in vitro. This work establishes an intramolecular NTD-LBD conformational change as an initial component of ligand-regulated NR function.

Original languageEnglish (US)
Pages (from-to)9802-9807
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number28
DOIs
StatePublished - Jul 12 2005

Keywords

  • Conformation change
  • Estrogen receptor
  • FQNLF
  • FRET
  • Nuclear receptor

ASJC Scopus subject areas

  • General

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