Interplay between allostery and intrinsic disorder in an ensemble

Area of Science:

• Biochemistry
• Molecular Biology
• Structural Biology

Background:

• Allostery is crucial for metabolic regulation and cell signaling, traditionally explained by structure-mediated 'action at a distance'.
• Intrinsically disordered proteins (IDPs) and segments are increasingly recognized in signaling pathways, challenging classical allostery models.
• IDPs offer finely tunable allosteric regulation, necessitating new frameworks to reconcile diverse allosteric phenomena.

Purpose of the Study:

• To investigate transferable ground rules reconciling classical and IDP-based allosteric regulation.
• To explore the role of intrinsically disordered N-terminal domains (NTDs) in glucocorticoid receptor (GR) function.
• To develop an ensemble allosteric model (EAM) applicable to various allosteric systems.

Main Methods:

• Studied different translational isoforms of the human glucocorticoid receptor (GR) with varying NTD lengths.
• Analyzed the thermodynamic properties of the intrinsically disordered NTD.
• Interpreted data within the framework of an ensemble allosteric model (EAM).

Main Results:

• The full-length intrinsically disordered NTD of GR comprises two distinct, coupled thermodynamic regions.
• The expanded EAM successfully explains context-dependent agonist/antagonist activity of steroid hormone receptor (SHR) ligands.
• Identified a mechanism for coupling distinct intrinsically disordered segments in SHRs and IDPs.

Conclusions:

• Intrinsically disordered proteins (IDPs) possess tunable allosteric regulatory capabilities.
• Ensemble allosteric models provide a unified framework for understanding allostery across different systems.
• Findings offer insights into the evolution and mechanisms of allosteric regulation in IDPs and SHRs.