Binding-induced folding of a natively unstructured transcription factor.

Transcription factors are central components of the intracellular regulatory networks that control gene expression. An increasingly recognized phenomenon among human transcription factors is the formation of structure upon target binding. Here, we study the folding and binding of the pKID domain of...

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Autores principales:	Adrian Gustavo Turjanski, J Silvio Gutkind, Robert B Best, Gerhard Hummer
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2008
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/bddcbccee18846ce8e35da3c6e082683
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spelling	oai:doaj.org-article:bddcbccee18846ce8e35da3c6e0826832021-11-25T05:41:20ZBinding-induced folding of a natively unstructured transcription factor.1553-734X1553-735810.1371/journal.pcbi.1000060https://doaj.org/article/bddcbccee18846ce8e35da3c6e0826832008-04-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/18404207/?tool=EBIhttps://doaj.org/toc/1553-734Xhttps://doaj.org/toc/1553-7358Transcription factors are central components of the intracellular regulatory networks that control gene expression. An increasingly recognized phenomenon among human transcription factors is the formation of structure upon target binding. Here, we study the folding and binding of the pKID domain of CREB to the KIX domain of the co-activator CBP. Our simulations of a topology-based Gō-type model predict a coupled folding and binding mechanism, and the existence of partially bound intermediates. From transition-path and Phi-value analyses, we find that the binding transition state resembles the unstructured state in solution, implying that CREB becomes structured only after committing to binding. A change of structure following binding is reminiscent of an induced-fit mechanism and contrasts with models in which binding occurs to pre-structured conformations that exist in the unbound state at equilibrium. Interestingly, increasing the amount of structure in the unbound pKID reduces the rate of binding, suggesting a "fly-casting"-like process. We find that the inclusion of attractive non-native interactions results in the formation of non-specific encounter complexes that enhance the on-rate of binding, but do not significantly change the binding mechanism. Our study helps explain how being unstructured can confer an advantage in protein target recognition. The simulations are in general agreement with the results of a recently reported nuclear magnetic resonance study, and aid in the interpretation of the experimental binding kinetics.Adrian Gustavo TurjanskiJ Silvio GutkindRobert B BestGerhard HummerPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Computational Biology, Vol 4, Iss 4, p e1000060 (2008)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Adrian Gustavo Turjanski J Silvio Gutkind Robert B Best Gerhard Hummer Binding-induced folding of a natively unstructured transcription factor.
description	Transcription factors are central components of the intracellular regulatory networks that control gene expression. An increasingly recognized phenomenon among human transcription factors is the formation of structure upon target binding. Here, we study the folding and binding of the pKID domain of CREB to the KIX domain of the co-activator CBP. Our simulations of a topology-based Gō-type model predict a coupled folding and binding mechanism, and the existence of partially bound intermediates. From transition-path and Phi-value analyses, we find that the binding transition state resembles the unstructured state in solution, implying that CREB becomes structured only after committing to binding. A change of structure following binding is reminiscent of an induced-fit mechanism and contrasts with models in which binding occurs to pre-structured conformations that exist in the unbound state at equilibrium. Interestingly, increasing the amount of structure in the unbound pKID reduces the rate of binding, suggesting a "fly-casting"-like process. We find that the inclusion of attractive non-native interactions results in the formation of non-specific encounter complexes that enhance the on-rate of binding, but do not significantly change the binding mechanism. Our study helps explain how being unstructured can confer an advantage in protein target recognition. The simulations are in general agreement with the results of a recently reported nuclear magnetic resonance study, and aid in the interpretation of the experimental binding kinetics.
format	article
author	Adrian Gustavo Turjanski J Silvio Gutkind Robert B Best Gerhard Hummer
author_facet	Adrian Gustavo Turjanski J Silvio Gutkind Robert B Best Gerhard Hummer
author_sort	Adrian Gustavo Turjanski
title	Binding-induced folding of a natively unstructured transcription factor.
title_short	Binding-induced folding of a natively unstructured transcription factor.
title_full	Binding-induced folding of a natively unstructured transcription factor.
title_fullStr	Binding-induced folding of a natively unstructured transcription factor.
title_full_unstemmed	Binding-induced folding of a natively unstructured transcription factor.
title_sort	binding-induced folding of a natively unstructured transcription factor.
publisher	Public Library of Science (PLoS)
publishDate	2008
url	https://doaj.org/article/bddcbccee18846ce8e35da3c6e082683
work_keys_str_mv	AT adriangustavoturjanski bindinginducedfoldingofanativelyunstructuredtranscriptionfactor AT jsilviogutkind bindinginducedfoldingofanativelyunstructuredtranscriptionfactor AT robertbbest bindinginducedfoldingofanativelyunstructuredtranscriptionfactor AT gerhardhummer bindinginducedfoldingofanativelyunstructuredtranscriptionfactor
_version_	1718414541014958080

Binding-induced folding of a natively unstructured transcription factor.

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