Abstract
Intrinsically disordered (ID) regions are frequently found in the activation domains of many transcription factors including nuclear hormone receptors. It is believed that these ID regions promote molecular recognition by creating large 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 glucocorticoid receptor'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.
Highlights
Glucocorticoid receptor (GR) mediates biological effects of glucocorticoids at the level of gene regulation [1]
Presence of trifluoroethanol (TFE) resulted in a concentration-dependent increase in helical content (Figure 1C). These results support the hypothesis that AF1 has a propensity to adopt helical structure and presence of trehalose can promote secondary structure formation in otherwise intrinsically disordered (ID) AF1 domain
We further examined the effects of trehalose-induced functional interaction of steroid receptor coactivator-1 (SRC-1) and GR AF1 using GR-responsive promoters, in transient transfection-based reporter assays in GR-deficient CV-1 cells
Summary
Glucocorticoid receptor (GR) mediates biological effects of glucocorticoids at the level of gene regulation [1]. Precisely how transcription is regulated by GR is largely unknown This is due, in part, to the lack of information about GR’s two transactivation function regions, AF1 and AF2 (Figure 1A). We are only beginning to understand structure and functions of AF1; in spite of the fact that AF1 serves as major transactivation domain for GR. This has hampered our complete understanding of how GR transmits its transcriptional signal from ligand to specific gene(s). 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 GR activity, is greatly enhanced
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