Folding of the glucocorticoid receptor N-terminal transactivation function: dynamics and regulation

The glucocorticoid receptor (GR) mediates biological effects of glucocorticoids at the level of gene regulation, and plays important roles in many aspects of physiology. In recent years, it has become quite evident that GR behaves very dynamically, controlled by its reversible interactions with a variety of coregulatory proteins at various DNA and non-DNA sites. The N-terminal activation function domain (AF1) of the GR exists in an intrinsically disordered (ID) state, which promotes molecular recognition by providing surfaces capable of binding specific target molecules. Several studies suggest that when in action, the GR AF1 gains structure. Thus, it is hypothesized that the GR AF1 domain may be structured in vivo, at least when directly involved in transcriptional activation. Our recent work supports this conclusion. We propose that by allowing AF1 to rapidly and reversibly adopt various configurations through structural arrangements, AF1 can create protein surfaces that are readily available for selective binding to coregulatory proteins, resulting in GR-mediated transcriptional regulation of target genes.