E. Brad Thompson
Center for Nuclear Receptors and Cell Signaling, Dept. of Biology and Biochemistry, University of Houston, TX 77204; Center for Structural Biology and Molecular Biophysics, Dept. of Biochemistry and Molecular Biology, Univ. of Texas Medical Branch, Galveston, TX 77551, USA
Regions of Intrinsic Disorder (ID) in otherwise folded proteins exist as large ensembles of structures. ID regions occur in proteins of prokaryotes and especially of eukaryotes, in which 30% of all proteins and 70% of transcription factors contain ID regions. The new Ensemble Allostery Model (EAM) provides a fresh, quantitative, thermodynamics-based model for allosteric behavior of ID proteins. We have employed the Glucocorticoid Receptor (GR) as a system to study the role of ID in the allosteric behavior of steroid hormone receptors, ligand-driven transcription factors. N-terminal (NTD), DNA-binding (DBD), hinge, and Ligand-binding (LBD) domains have been mapped to the GR’s primary sequence. The NTD and hinge are largely ID. The GR NTD accounts for about 70% of the GR’s transcription-regulating activity. By using protective osmolytes, we showed that the GR NTD could be induced to fold and strongly bind certain co-factor proteins. Extension of this initial finding led to development of the EAM and new discoveries of the mechanisms of GR NTD allosteric behavior. Signal transducing proteins usually contain ID regions; thus, application of the EAM to other relevant proteins during the development and use of drugs should prove of great value.
Keywords: Disorder, proteins, allosteric, prokaryotes.