INTRINSIC DISORDER AND ALLOSTERY IN GLUCOCORTICOID RECEPTOR

Jing Li

Program in Cellular and Molecular Medicine, Boston Children’s Hospital and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA

Abstract

Intrinsically disordered (ID) proteins are sensitive regulators of cell functions. Allostery is transmittance of a perturbation at one region to distant sites of the same molecule, allowing for precise control of macromolecular function. Nature preferentially uses both ID regions and allostery to regulate protein function, as observed in transcription factors.

We investigated the allostery mediated by the ID regions in human glucocorticoid receptor (GR). Through studies on eight GR translational isoforms, we found that the ID N terminal domain is composed of two functionally distinct regions, unfavorably coupled with each other, and both are favorably coupled to the DNA binding domain. Based on these constraints, an Ensemble Allosteric Model (EAM) was built for GR and reasonable thermodynamic parameters were found to describe both the transcriptional activity and binding affinity of the isoforms. We revealed that GR uses these competing energetic couplings, which are modulated in different translational isoforms, to provide tunable responses to environmental cues.

In the context of the EAM predictions, mutagenesis was utilized to pinpoint the molecular basis of allostery, which paves a way for allosteric drug design. This study suggests a unifying strategy to investigate thermodynamics and the molecular basis of allostery in any complicated system.

Keywords: Proteins, allostery, thermodynamics, molecular, system.