Related Experiment Video

Updated: Sep 26, 2025

Detecting the Ligand-binding Domain Dimerization Activity of Estrogen Receptor Alpha Using the Mammalian Two-Hybrid Assay
09:07

Detecting the Ligand-binding Domain Dimerization Activity of Estrogen Receptor Alpha Using the Mammalian Two-Hybrid Assay

Published on: December 19, 2018

6.5K

Allosteric interactions prime androgen receptor dimerization and activation

Elizabeth V Wasmuth1, Arnaud Vanden Broeck2, Justin R LaClair3

  • 1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Laboratory of Protein and Nucleic Acid Chemistry, The Rockefeller University, New York, NY 10065, USA.

Molecular Cell
|April 21, 2022
PubMed

Insights

Androgen receptor (AR) forms dimers to bind DNA cooperatively, a mechanism crucial for prostate development and cancer. This AR DNA-binding interface is targeted in disease and influenced by cofactors like ERG.

Area of Science:

  • Molecular biology
  • Structural biology
  • Genetics

Background:

  • The androgen receptor (AR) is vital for prostate development and male characteristics.
  • AR hyperactivation drives advanced prostate cancers, involving gene amplification and cofactor interactions.
  • Mechanisms of AR-DNA binding and cofactor cooperation remain unclear.

Purpose of the Study:

  • To elucidate the structural basis of androgen receptor (AR) DNA binding and cooperative interactions.
  • To investigate the role of AR domains and cofactors in DNA binding.
  • To understand how AR structural dynamics contribute to prostate development and cancer.

Main Methods:

  • Single-particle cryo-electron microscopy (cryo-EM) was used to determine AR-DNA complex structures.
  • Analysis of three distinct AR-DNA conformations.
  • Identification of allosteric surfaces and cofactor interactions.

Main Results:

  • AR forms a non-obligate dimer utilizing an ancestral interface for cooperative DNA binding.
  • Novel allosteric surfaces were identified, implicated in androgen insensitivity syndrome.
  • The cofactor ERG and DNA-binding motifs reinforce AR's cooperative DNA binding.
  • Evidence suggests the AR dimer interface is plastic, potentially favoring transactivation over DNA binding.

Conclusions:

  • AR's cooperative DNA binding is mediated by a flexible dimer interface, repurposed from ancestral receptors.
  • Dysregulation of this interface is linked to androgen insensitivity and prostate cancer progression.
  • Fine-tuning AR cooperative interactions impacts both normal development and disease states.
Keywords:
allosterycooperativitynuclear receptorprostate cancertranscription factors

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