Abstract 4532: Induced folding of the glucocorticoid receptor's AF1 domain facilitates its interaction with steroid receptor coactivator-1
Authors: Khan Shagufta H. , Ling Jun , Kumar Raj 
Published: June 2012

The mechanism by which glucocorticoids brings about apoptotic cell death of lymphoid cells is still not well understood. However, it has been established that ligand-activated glucocorticoid receptor (GR) regulates transcription of target genes by binding to site-specific DNA and/or coregulatory proteins. Like other members of the steroid hormone receptors (SHRs), the GR possesses a modular structure characterized by three major functional domains: N-terminal domain (NTD), DNA binding domain (DBD), and ligand binding domain (LBD). The transactivation activity of SHRs is mainly controlled by two activation function domains, AF1 and AF2 located in the NTD and LBD, respectively. The precise mechanism by which SHRs regulate the transcription of the target genes is largely unknown. This is, in part, due to the lack of structural and functional information about AF1 domain. Due to the availability of the LBD structure, the relevant structural and functional properties of AF2 have been well characterized whereas it is nebulous in case of AF1 due to unavailability of its 3-D structure. The GR AF1 exists as an ensemble of largely unstructured conformers or intrinsically disordered (ID). The GR AF1 recruits other coregulatory proteins, including proteins from the basal transcriptional machinery, e.g. TATA box binding protein (TBP) by creating binding surfaces for these proteins. Other studies have also shown that transactivation domains of several transcription factors including SHRs undergo a disorder/order transition upon interaction with proteins from the basal transcriptional machinery. We have earlier shown that conditional folding of the GR AF1 is the key for its interactions with its critical coactivator proteins. It is interesting that the ID GR AF1 directly interacts with the TBP, the critical protein that forms the basis for the multiprotein transcription initiation complex. However, the precise mechanism of this process is unknown. One possibility may be that TBP binding-induced structured conformation in AF1 is involved in creating a platform for the GR AF1-associated coactivators. In this study we tested whether TBP binding induces structure formation in the GR AF1 such that AF1's interaction with SRC-1, a critical coactivator which is important for GR-mediated transcriptional activity, is facilitated. Our data show that TBP binding induced structure formation in the GR AF1facilitates its interaction with SRC-1, and subsequent AF1-mediated transcriptional activity. Our results provide a potential mechanism through which GR and other SHRs may regulate the expression of the GR-target genes, information essential to understand how specific signals are passed from the receptor to target genes.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4532. doi:10.1158/1538-7445.AM2011-4532