Osmolyte-Induced Folding of an Intrinsically Disordered Activation Function Subdomain of Glucocorticoid Receptor

Abstract

Intrinsically disordered (ID) regions are disproportionately higher in cell-signaling proteins, suggesting an important role in their regulatory capacity. Activation domains of many transcription factors exist in ID conformation(s). It has been suggested that large flexible regions in ID activation domains have an advantage over proteins with ordered conformations such that ID regions/domains can make more efficient interactions with their target partners. The major activation function-1 (AF1) region, located in the N-terminal domain of several steroid receptors, including the glucocorticoid receptor (GR) possess ID sequences. Recently, we reported that osmolytes fold AF1 into functionally active conformation. Most of known AF1:coregulatory proteins interactions take place in a core subdomain (AF1_C) that is indispensible for AF1-mediated GR activity. However, it is not known whether osmolytes can induce functionally folded conformation in AF1_C. In this study we have found that a naturally occurring osmolyte, trimethylamine-N-oxide, can cooperatively fold AF1_C into a compact structure.

Key words::

• Trimethylamine-N-oxide
• Activation function
• Cooperative folding
• Glucocorticoid receptor
• Intrinsically disordered

ACKNOWLDGMENTS

Grant support was given by NIH NIDDK 5R01DK058829-07 (R.K.). J. M. Serrette and A. K. Mishra provided technical help during some of the experiments, and Justin J. Robert helped with PONDR analysis.