Ensemble allosteric model: energetic frustration within the intrinsically disordered glucocorticoid receptor

White, Jordan T.; Li, Jing; Grasso, Emily M; Wrabl, James O.; Hilser, Vincent J.

doi:10.1098/rstb.2017.0175

Cited by 33 publications

(36 citation statements)

References 75 publications

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“…The picture that has emerged from various domains of biology is that allostery involves the interplay of a spectrum of dynamically linked states [ 11 – 17 ]. In some systems, it is straightforward to partition these states into the physiologically relevant categories; for example, CRP naturally divides into the cAMP unbound, singly bound, and doubly bound states as well as the DNA bound and unbound states.…”

Section: Introductionmentioning

confidence: 99%

Theoretical analysis of inducer and operator binding for cyclic-AMP receptor protein mutants

Einav¹,

Duque²,

Phillips³

2018

PLoS ONE

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Allosteric transcription factors undergo binding events at inducer binding sites as well as at distinct DNA binding domains, and it is difficult to disentangle the structural and functional consequences of these two classes of interactions. We compare the ability of two statistical mechanical models—the Monod-Wyman-Changeux (MWC) and the Koshland-Némethy-Filmer (KNF) models of protein conformational change—to characterize the multi-step activation mechanism of the broadly acting cyclic-AMP receptor protein (CRP). We first consider the allosteric transition resulting from cyclic-AMP binding to CRP, then analyze how CRP binds to its operator, and finally investigate the ability of CRP to activate gene expression. We use these models to examine a beautiful recent experiment that created a single-chain version of the CRP homodimer, creating six mutants using all possible combinations of the wild type, D53H, and S62F subunits. We demonstrate that the MWC model can explain the behavior of all six mutants using a small, self-consistent set of parameters whose complexity scales with the number of subunits, providing a significant benefit over previous models. In comparison, the KNF model not only leads to a poorer characterization of the available data but also fails to generate parameter values in line with the available structural knowledge of CRP. In addition, we discuss how the conceptual framework developed here for CRP enables us to not merely analyze data retrospectively, but has the predictive power to determine how combinations of mutations will interact, how double mutants will behave, and how each construct would regulate gene expression.

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Section: Introductionmentioning

confidence: 99%

Theoretical analysis of inducer and operator binding for cyclic-AMP receptor protein mutants

Einav¹,

Duque²,

Phillips³

2018

PLoS ONE

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“…Specifically, thermodynamic analysis of the stability and DNA binding affinities of various isoforms of GR (13), revealed that the GR A isoform exists in a frustrated state, wherein the Rdomain ( Fig. 6A) decreases the probability of the GR A being in its active conformation (29). This occurs because the R-domain is both positively coupled and, therefore, stabilized by the DBD, and also negatively coupled, therefore destabilizing, to the F-domain, which is responsible for interaction with TSG101cc.…”

Section: The Effect Of Energetic Frustration On Tsg101:gr a Bindingmentioning

confidence: 99%

Tumor susceptibility gene-101 regulates glucocorticoid receptor through disorder-mediated allostery

White

Rives²,

Tharp

et al. 2020

Preprint

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Tumor Susceptibility Gene-101 (TSG101) is involved in endosomal maturation and has been implicated in the transcriptional regulation of several steroid hormone receptors (SHRs), although a detailed characterization of such regulation has yet to be conducted. Here we directly measure binding of TSG101 to one SHR, glucocorticoid receptor (GR). Using biophysical and cellular assays, we show that the coiled-coil domain of TSG101; 1) binds and folds the disordered N-terminal domain (NTD) of GR, 2) upon binding, improves DNA-binding of GR in vitro, and 3) enhances the transcriptional activity of GR in vivo. Our findings suggest that TSG101 is a bona fide transcriptional co-regulator of GR.

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“…A more recent model of the allosteric process is named EAM (ensemble allostery model) (Hilser et al, 2012;Tsai and Nussinov, 2014;Choi et al, 2015;White et al, 2018). It provides a generalization of both MWC and KNF models, allowing the treatment of a set of different populated conformational states (Hilser et al, 2012).…”

Section: Models Of Allosteric Phenomenonmentioning

confidence: 99%

A Time-Dependent Quantum Approach to Allostery and a Comparison With Light-Harvesting in Photosynthetic Phenomenon

Villani

2020

Front. Mol. Biosci.

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The allosteric effect is one of the most important processes in regulating the function of proteins, and the elucidation of this phenomenon plays a significant role in understanding emergent behaviors in biological regulation. In this process, a perturbation, generated by a ligand in a part of the macromolecule (the allosteric site), moves along this system and reaches a specific (active) site, dozens of Ångströms away, with a great efficiency. The dynamics of this perturbation in the macromolecule can model precisely the allosteric process. In this article, we will be studying the general characteristics of allostery, using a time-dependent quantum approach to obtain rules that apply to this kind of process. Considering the perturbation as a wave that moves within the molecular system, we will characterize the allosteric process with three of the properties of this wave in the active site: (1) t a , the characteristic time for reaching that site, (2) A a , the amplitude of the wave in this site, and (3) B a , its corresponding spectral broadening. These three parameters, together with the process mechanism and the perturbation efficiency in the process, can describe the phenomenon. One of the main purposes of this paper is to link the parameters t a , A a , and B a and the perturbation efficiency to the characteristics of the system. There is another fundamental process for life that has some characteristics similar to allostery: the light-harvesting (LH) process in photosynthesis. Here, as in allostery, two distant macromolecular sites are involvedtwo sites dozens of Ångströms away. In both processes, it is particularly important that the perturbation is distributed efficiently without dissipating in the infinite degrees of freedom within the macromolecule. The importance of considering quantum effects in the LH process is well documented in literature, and the quantum coherences are experimentally proven by time-dependent spectroscopic techniques. Given the existing similarities between these two processes in macromolecules, in this work, we suggest using Quantum Mechanics (QM) to study allostery.

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Ensemble allosteric model: energetic frustration within the intrinsically disordered glucocorticoid receptor

Cited by 33 publications

References 75 publications

Theoretical analysis of inducer and operator binding for cyclic-AMP receptor protein mutants

Theoretical analysis of inducer and operator binding for cyclic-AMP receptor protein mutants

Tumor susceptibility gene-101 regulates glucocorticoid receptor through disorder-mediated allostery

A Time-Dependent Quantum Approach to Allostery and a Comparison With Light-Harvesting in Photosynthetic Phenomenon

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