A hotspot for conformational heterogeneity driven by proline isomerisation in the androgen receptor disordered N-terminal domain

The androgen receptor is a hormone-dependent transcription factor that regulates a wide range of physiological processes and plays a pivotal role in the development of prostate cancer. Its 555-residue, intrinsically disordered, N-terminal domain is involved in the modulation of transcriptional activity by recruiting co-regulators and mediating the formation of biomolecular condensates. This study reports on the characterisation of a conserved domain located in the C-terminal region of the androgen receptor N-terminal domain, at atomic level, using nuclear magnetic resonance spectroscopy. This proline rich region exhibits extensive conformational heterogeneity driven by highly populated cis proline conformers that are stabilised through interactions with adjacent aromatic residues. We demonstrate that the cis-proline population is modulated by phosphorylation as well as cancer-associated mutations. This suggests that proline driven conformational heterogeneity at the C-terminal region of androgen receptor N-terminal domain is involved in the regulatory function of this transcription factor.