Seminario impartido por Eva Estébanez Perpiñá, de la Universidad de Barcelona
Oligomerization of androgen (AR) and glucocorticoid (GR) receptors remains disputed. We identified four distinct homodimerization interfaces on the GR-LBD surface, which can associate into 20 topologically different homodimers. Biologically relevant GR homodimers were identified by studying a battery of GR point mutants including crosslinking assays in solution, quantitative fluorescence microscopy in living cells, and transcriptomic analyses. Our results highlight the relevance of non-canonical dimerization modes for GR and illustrates the unique flexibility of GR´s LBD and suggests different dimeric conformations within cells. In the case of AR, The contribution of LBD dimerization to the physiological activity of the receptor has remained controversial for a long time. We presented the crystal structure of an AR-LBD homodimer for the first time, along with biochemical and functional evidence of its relevance in vivo. The dimerization of the AR is crucial for its activity, for the pharmacological outcome to major antiandrogen blockbusters for prostate cancer patients and to understand rare sex development disorders in children and a rare neurodegeneration in adults. We have recently also thoroughly studied the effects of selected mutations that span the complete dimer interface of AR-LBD using x-ray crystallography in combination with in vitro, in silico, and cell-based assays. We show that these variants alter AR-dependent transcription and responses to anti-androgens by inducing a previously undescribed allosteric switch in the AR-LBD that increases exposure of a major methylation target, Arg761. Together, our results reveal allosteric coupling of AR dimerization and posttranslational modifications as a disease mechanism with implications for precision medicine.
Fecha del seminario: 24/01/2024 12:00
Lugar del seminario: salón de actos IQF
Ponente del seminario: Eva Estébanez Perpiñá
