Abstract 4552: Naturally occurring osmolyte, trehalose induces a functionally active conformation in an intrinsically disordered transactivation function domain (AF1) of the Glucocorticoid Receptor

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Due to the ability of glucocorticoids to prevent the growth and to cause apoptotic death of malignant cells, they are a mainstay of therapy for many lymphomas and leukemias. Glucocorticoid receptor (GR) mediates the biological effects of glucocorticoids at the level of gene regulation. To initiate transcription of target gene(s), GR interacts with its response element DNA, and/or with various coregulatory proteins. However, specific interaction surfaces of GR with its coregulators are not well understood. Consequently, precisely how transcription is regulated by GR is largely unknown. This is due, in part, to the lack of information about GR's major transactivation function region, AF1 located in the N-terminal domain. The major obstacle in determining the structure of AF1 has been due to its intrinsically disordered (ID) conformation, frequently found in the activation domains of many transcription factors, and it is believed that ID nature of these activation domains promote molecular recognition by creating large interaction surfaces suitable for interactions with their specific protein binding partners, which is a critical component of gene regulation by transcription factors. It has been hypothesized that conditional folding of these activation domains may be a prerequisite for their efficient interaction with specific coregulatory proteins, and subsequent transcriptional activity leading to the regulation of target gene(s). In this study, we tested whether a naturally occurring osmolyte, trehalose can promote functionally ordered conformation in the GR's major activation function domain, AF1, which is found to exist as an ID protein, and requires an efficient interaction with coregulatory proteins for optimal activity. Our data show that trehalose induces an ordered conformation in AF1 such that its interaction with steroid receptor coactivator-1 (SRC-1), a critical coregulator of glucocorticoid receptor's activity, is greatly enhanced. Our results may provide a mechanism for cell-type specificity of the effects of GR in gene regulation. 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 4552. doi:10.1158/1538-7445.AM2011-4552