Implications of Order Disorder Transitions in the Androgen Receptor for the Onset and Treatment of Late Stage Prostate Cancer

Abstract

The nuclear hormone receptor androgen receptor (AR) is a transcription factor of 919 amino acids activated by androgens that regulates the development of the male sexual phenotype [1]. It is composed of three domains: a flexible N-terminal intrinsically disordered transactivation domain that interacts with the transcription machinery, a DNA-binding domain that binds specific DNA sequences adjacent to genes regulated by AR and a C-terminal domain that upon androgen binding undergoes a structural change that activates the protein.To understand the structural basis of transcription activation by the N-terminal domain of AR we have used NMR. We have in particular characterized the interaction between the N-terminal intrinsically disordered transactivation domain and the C-terminal domain of subunit 1 of TFIIF, a general transcription factor tightly associated with RNA polymerase and therefore considered part of the transcription machinery [2].We find that this protein-protein interaction induces structure in an otherwise disordered region of sequence of this domain and have produced a structural model for the complex that we have validated both in vitro and in vivo. As we will show our results provide information about the mechanism by which AR activates transcription in castration resistant prostate cancer, a late stage of the disease for which there currently is no treatment.