645.3 - Structural studies of an androgen receptor complex reveal modes of allosteric regulation

Elizabeth Wasmuth (Memorial Sloan Kettering Cancer Center, The Rockefeller University), Arnaud Vanden Broeck (The Rockefeller University), Justin LaClair (Memorial Sloan Kettering Cancer Center), Kayla Lawrence (Memorial Sloan Kettering Cancer Center), Elizabeth Hoover (Memorial Sloan Kettering Cancer Center), Kyrie Pappas (Memorial Sloan Kettering Cancer Center), Biran Wang (Memorial Sloan Kettering Cancer Center), Katia Manova-Todorova (Memorial Sloan Kettering Cancer Center), Susan Weintraub (UT Health San Antonio), Sebastian Klinge (The Rockefeller University), Charles Sawyers (Memorial Sloan Kettering Cancer Center)

The androgen receptor (AR) is the master transcription factor governing gene expression programs required for prostate epithelium development and male phenotype maintenance. AR misregulation is a hallmark of prostate cancer where AR hyperactivation and transcriptome expansion occur in part through AR amplification and interaction with oncoprotein cofactors. Despite its biological importance, how AR’s domains and cofactors cooperate to bind DNA have remained elusive. We isolated three conformations of AR bound to DNA showing AR forms a non-obligate dimer, with the buried dimer interface utilized by ancestral steroid receptors repurposed to facilitate cooperative DNA binding. We identify novel allosteric surfaces which are compromised in androgen insensitivity syndrome, and reinforced by AR’s oncoprotein cofactor, ERG, and DNA binding motifs. Finally, we present evidence this plastic dimer interface was adopted for transactivation at the expense of DNA binding. Our work highlights how fine-tuning AR’s cooperative interactions translate to consequences in development and disease. 

Support or Funding Information

EVW is a MOSAIC K99 recipient (GM140264) and Prostate Cancer Foundation Young Investigator. CLS is a Howard Hughes Medical Institute Investigator is supported by the National Cancer Institute.