Binding‐folding induced regulation of the AF1 transactivation domain of the glucocorticoid receptor

Abstract

The precise mechanism by which the glucocorticoid receptor (GR) regulates the transcription of the target genes is largely unknown. This is, in part, due to the lack of structural and functional information about its AF1 transactivation domain, which exists as an ensemble of largely unstructured conformers or intrinsically disordered (ID). It has been shown that transactivation domains of several transcription factors undergo a disorder/order transition upon interaction with proteins from the basal transcriptional machinery. It is interesting that the ID GR AF1 directly interacts with the TATA box binding protein (TBP), the critical protein that forms the basis for the multiprotein transcription initiation complex. However, the precise mechanism of this process is unknown. In this study we tested whether TBP binding induces structure formation in the GR AF1 such that AF1's interaction with steroid receptor coactivator‐1 (SRC‐1), a critical coactivator which is important for GR‐mediated transcriptional activity, is facilitated. Our data show that TBP binding induces structure formation in otherwise ID AF1such that its interaction with SRC‐1, and subsequent AF1‐mediated transcriptional activity is significantly enhanced. Our results may provide a potential mechanism through which GR passes its signals to regulate the expression of its specific target genes. Supported by a grant from NIH (DK058829).