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Entropic Control of an Excited Folded-Like Conformation in a Disordered Protein Ensemble
Published in Academic Press
2018
PMID: 29885328
Volume: 430
   
Issue: 17
Pages: 2688 - 2694
Abstract
Many intrinsically disordered proteins switch between unfolded and folded-like forms in the presence of their binding partner. The possibility of a pre-equilibrium between the two macrostates is challenging to discern given the complex conformational landscape. Here, we show that CytR, a disordered DNA-binding domain, samples a folded-like excited state in its native ensemble through equilibrium multi-probe spectroscopy, kinetics and an Ising-like statistical mechanical model. The population of the excited state increases upon stabilization of the native ensemble with an osmolyte, while decreasing with increasing temperatures. A conserved proline residue, the mutation of which weakens the binding affinity to the target promoter, is found to uniquely control the population of the minor excited state. Semi-quantitative statistical mechanical modeling reveals that the conformational diffusion coefficient of disordered CytR is an order of magnitude slower than the estimates from folded domains. The osmolyte and proline mutation smoothen and roughen up the landscape, respectively, apart from modulation of populations. Our work uncovers general strategies to probe for excited structured states in disordered ensembles, and to measure and modulate the roughness of the disordered landscapes, inter-conversion rates of species and their populations. © 2018 The Author(s)
About the journal
JournalJournal of Molecular Biology
PublisherAcademic Press
ISSN00222836
Open AccessYes
Concepts (29)
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    Dna binding protein
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    Proline
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    PROTEIN CYTR
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    Unclassified drug
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    DNA
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    Intrinsically disordered protein
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    Protein binding
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    Article
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    Binding affinity
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    Controlled study
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    Diffusion coefficient
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    Kinetics
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    Priority journal
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    Promoter region
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    Protein conformation
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    Protein domain
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    Protein folding
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    Spectroscopy
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    Statistical model
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    Temperature
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    Thermodynamics
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    Chemistry
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    Entropy
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    Genetics
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    Metabolism
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    Molecular model
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    Mutation
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    Intrinsically disordered proteins
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    Models, molecular