Allostery is a biological phenomenon of critical importance in metabolic regulation and cell signalling. The fundamental premise of classical models that describe allostery is that structure mediates ‘action at a distance’. Recently, this paradigm has been challenged by the enrichment of IDPs (intrinsically disordered proteins) or ID (intrinsically disordered) segments in transcription factors and signalling pathways of higher organisms, where an allosteric response from external signals is requisite for regulated function. This observation strongly suggests that IDPs elicit the capacity for finely tunable allosteric regulation. Is there a set of transferable ground rules that reconcile these disparate allosteric phenomena? We focus on findings from the human GR (glucocorticoid receptor) which is a nuclear transcription factor in the SHR (steroid hormone receptor) family. GR contains an intrinsically disordered NTD (N-terminal domain) that is obligatory for transcription activity. Different GR translational isoforms have various lengths of NTD and by studying these isoforms we found that the full-length ID NTD consists of two thermodynamically distinct coupled regions. The data are interpreted in the context of an EAM (ensemble allosteric model) that considers only the intrinsic and measurable energetics of allosteric systems. Expansion of the EAM is able to reconcile the paradox that ligands for SHRs can be agonists and antagonists in a cell-context-dependent manner. These findings suggest a mechanism by which SHRs in particular, and IDPs in general, may have evolved to couple thermodynamically distinct ID segments. The ensemble view of allostery that is illuminated provides organizing principles to unify the description of all allosteric systems and insight into ‘how’ allostery works.
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October 2012
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Conference Article|
September 19 2012
Interplay between allostery and intrinsic disorder in an ensemble
Hesam N. Motlagh;
Hesam N. Motlagh
1
*T.C. Jenkins Department of Biophysics, Johns Hopkins University, Baltimore, MD 21218, U.S.A.
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Jing Li;
Jing Li
1
*T.C. Jenkins Department of Biophysics, Johns Hopkins University, Baltimore, MD 21218, U.S.A.
†Department of Biology, Johns Hopkins University, Baltimore, MD 21218, U.S.A.
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E. Brad Thompson;
E. Brad Thompson
‡Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX 77204-5056, U.S.A.
§Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555-1068, U.S.A.
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Vincent J. Hilser
Vincent J. Hilser
2
*T.C. Jenkins Department of Biophysics, Johns Hopkins University, Baltimore, MD 21218, U.S.A.
†Department of Biology, Johns Hopkins University, Baltimore, MD 21218, U.S.A.
2To whom correspondence should be addressed (emailHilser@jhu.edu).
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Publisher: Portland Press Ltd
Received:
June 27 2012
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© The Authors Journal compilation © 2012 Biochemical Society
2012
Biochem Soc Trans (2012) 40 (5): 975–980.
Article history
Received:
June 27 2012
Citation
Hesam N. Motlagh, Jing Li, E. Brad Thompson, Vincent J. Hilser; Interplay between allostery and intrinsic disorder in an ensemble. Biochem Soc Trans 1 October 2012; 40 (5): 975–980. doi: https://doi.org/10.1042/BST20120163
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