LAUSR

Androgen receptor (AR) splice variants are described as one of the potential drivers of lethal castration-resistant prostate cancer. Androgen receptor splice variant 7 (ARv7) is the most commonly observed isoform and strongly correlates with resistance to second-generation antiandrogens. Despite this clinical evidence, the interplay between ARv7 and the highly expressed full-length AR (ARfl) remains unclear. In this work we show that ARfl/ARv7 heterodimers readily form in the nucleus via an intermolecular N/C interaction that brings the four termini of the proteins in close proximity. Combining FRET and FRAP we demonstrate that these heterodimers undergo conformational changes following DNA binding indicating dynamic nuclear receptor interaction. Although transcriptionally active, ARv7 can only form short-term interactions with DNA at highly accessible, high-occupancy ARfl binding sites. Dimerization with ARfl does not affect ARv7 binding dynamics suggesting that DNA binding occupancy is determined by the individual protein monomers and not the homo- or heterodimer complex. Overall, these biophysical studies reveal detailed properties of ARv7 dynamics as both a homodimer or heterodimer with ARfl.