Disordered allostery: lessons from glucocorticoid receptor

Allostery is a biological regulation mechanism of significant importance in cell signaling, metabolism, and disease. Although the ensemble basis of allostery has been known for years, only recently has emphasis shifted from interpreting allosteric mechanism in terms of discrete structural pathways to ones that focus on the statistical nature of the signal propagation process, providing a vehicle to unify allostery in structured, dynamic, and disordered systems. In particular, intrinsically disordered (ID) proteins (IDPs), which lack a unique, stable structure, have been directly demonstrated to exhibit allostery in numerous systems, a reality that challenges traditional structure-based models that focus on allosteric pathways. In this chapter, we will discuss the historical context of allostery and focus on studies from human glucocorticoid receptor (GR), a member of the steroid hormone receptor (SHR) family. The numerous translational isoforms of the disordered N-terminal domain of GR consist of coupled thermodynamic domains that contribute to the delicate balance of states in the ensemble and hence in vivo activity. The data are quantitatively interpreted using the ensemble allosteric model (EAM) that considers only the intrinsic and measurable energetics of allosteric systems. It is demonstrated that the EAM provides mechanistic insight into the distribution of states in solution and provides an interpretation for how certain translational isoforms of GR display enhanced and repressed transcriptional activities. The ensemble nature of allostery illuminated from these studies lends credence to the EAM and provides ground rules for allostery in all systems.