Allosteric Interactions Prime Androgen Receptor Dimerization And Activation

The study "Allosteric interactions prime androgen receptor dimerization and activation" investigates the androgen receptor (AR), a steroid receptor and master transcription factor that is crucial for the development of prostate epithelium, muscle tissue, and the male phenotype. Misregulation of AR is a key feature of several cancers, including prostate cancer. The researchers used reconstitution biochemistry and single particle cryo-electron microscopy to isolate three conformational states of AR bound to DNA. They found that AR forms a non-obligate dimer, with the buried dimer interface used by related ancestral nuclear receptors repurposed to facilitate cooperative DNA binding. They identified surfaces bridging AR's domains responsible for allosteric communication, which are compromised in partial androgen insensitivity syndrome (PAIS), and are reinforced by AR's oncoprotein cofactor, ERG, and DNA binding site motifs. The study suggests that this plastic dimer interface for transcriptional activation may have been adopted by AR at the expense of DNA binding, highlighting how fine-tuning of AR's cooperative interactions can have implications in development and disease.