Regulation of Androgen Receptor Activity by Transient Interactions of Its Transactivation Domain with General Transcription Regulators

The androgen receptor is a transcription factor that plays a key role in the development of prostate cancer, and its interactions with general transcription regulators are therefore of potential therapeutic interest. The mechanistic basis of these interactions is poorly understood due to the intrinsically disordered nature of the transactivation domain of the androgen receptor and the generally transient nature of the protein-protein interactions that trigger transcription. Here, we identify a motif of the transactivation domain that contributes to transcriptional activity by recruiting the C-terminal domain of subunit 1 of the general transcription regulator TFIIF. These findings provide molecular insights into the regulation of androgen receptor function and suggest strategies for treating castration-resistant prostate cancer. [Display omitted] •A short motif in transactivation unit 5 recruits the transcription machinery to the AR•The motif is intrinsically disordered but folds into a helix upon binding•Phosphorylation of Ser 424 of AR is essential for recruitment•The interaction may be a target for castration-resistant prostate cancer Identifying ways to inhibit the androgen receptor (AR) is key for developing treatments for castration-resistant prostate cancer. Here, De Mol, Szulc et al. show that AR activity relies on transient interactions of a disordered motif with the transcription machinery and suggest therapeutic strategies for this disease.