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Detecting the Ligand-binding Domain Dimerization Activity of Estrogen Receptor Alpha Using the Mammalian Two-Hybrid Assay
Published on: December 19, 2018
Modulation of androgen receptor activation function 2 by testosterone and dihydrotestosterone
Emily B Askew1, Robert T Gampe, Thomas B Stanley
1Curriculum in Toxicology, Laboratories for Reproductive Biology, Lineberger Comprehensive Cancer Center, Department of Pediatrics, University of North Carolina, Chapel Hill 27599, USA.
The Journal of Biological Chemistry
|June 27, 2007
Summary
Testosterone (T) is a weaker androgen than dihydrotestosterone (DHT) due to less favorable interactions with the androgen receptor's (AR) activation function 2 (AF2). A prostate cancer mutation rescues T
Area of Science:
- Molecular Endocrinology
- Structural Biology
- Prostate Cancer Research
Background:
- Androgen receptor (AR) transcriptional activity is crucial for male development, mediated by testosterone (T) and dihydrotestosterone (DHT).
- DHT is a more potent androgen than T, but the molecular basis for this difference is not fully understood.
Purpose of the Study:
- To investigate the molecular mechanisms underlying the differential activity of T and DHT on AR.
- To elucidate the structural basis for T's weaker transcriptional activation compared to DHT.
Main Methods:
- Determined crystal structures of the AR ligand-binding domain complexed with T or DHT and AR interaction motifs.
- Utilized biophysical techniques to assess ligand-receptor interactions and dissociation rates.
Main Results:
- T and DHT exhibit similar binding affinities within the AR ligand-binding pocket.
- T induces weaker interactions with AR motifs at activation function 2 (AF2) compared to DHT.
- A specific prostate cancer mutation (H874Y) rescues T's activity by enhancing AF2 interactions.
Conclusions:
- T is a weaker androgen than DHT due to less effective FXXLF and LXXLL motif interactions at AR's AF2.
- AR mutations can restore T's potency, highlighting the role of specific structural interactions in androgen activity.
- Understanding these molecular differences is vital for research into AR-mediated diseases like prostate cancer.
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