Allosteric interactions prime androgen receptor dimerization and activation

• Published in: Molecular cell 2022-06, Vol.82 (11), p.2021-2031.e5
• Main Authors: Wasmuth, Elizabeth V., Broeck, Arnaud Vanden, LaClair, Justin R., Hoover, Elizabeth A., Lawrence, Kayla E., Paknejad, Navid, Pappas, Kyrie, Matthies, Doreen, Wang, Biran, Feng, Weiran, Watson, Philip A., Zinder, John C., Karthaus, Wouter R., de la Cruz, M. Jason, Hite, Richard K., Manova-Todorova, Katia, Yu, Zhiheng, Weintraub, Susan T., Klinge, Sebastian, Sawyers, Charles L.
• Format: Article
• Language: English
• Subjects: allostery; Biochemistry, biophysics & molecular biology; Biochimie, biophysique & biologie moléculaire; cooperativity; Cryoelectron Microscopy; Dimerization; DNA; DNA - metabolism; Humans; Life sciences; Male; nuclear receptor; prostate cancer; Prostatic Neoplasms - genetics; Receptors, Androgen; Receptors, Androgen - genetics; Receptors, Androgen - metabolism; Receptors, Androgen/genetics/metabolism; Sciences du vivant; transcription factors; Transcriptional Activation
• ISSN: 1097-2765; 1097-4164; 1097-4164
• DOI: 10.1016/j.molcel.2022.03.035

The androgen receptor (AR) is a nuclear receptor that governs gene expression programs required for prostate development and male phenotype maintenance. Advanced prostate cancers display AR hyperactivation and transcriptome expansion, in part, through AR amplification and interaction with oncoprotein cofactors. Despite its biological importance, how AR domains and cofactors cooperate to bind DNA has remained elusive. Using single-particle cryo-electron microscopy, we isolated three conformations of AR bound to DNA, showing that 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 by DNA-binding motifs. Finally, we present evidence that this plastic dimer interface may have been 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. [Display omitted] •DNA-bound AR dimers exhibit conformational plasticity•Allostery between AR domains promotes DNA binding and transactivation•Allosteric surfaces are mutated in partial androgen insensitivity syndrome•The ERG oncoprotein and AR’s hinge enhance binding to non-canonical DNA sequences Molecular features regulating DNA binding and the transactivation activities of the androgen receptor (AR) and the greater steroid receptor family have remained elusive. Using cryo-EM and mass spectrometry, Wasmuth et al. reveal a tunable mode of dimerization and define allosteric surfaces important for AR activities and development.