PEST Control of Molecular Stripping of NFκB from DNA Transcription Sites

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We recently proposed a model for IκBα-mediated molecular stripping of NFκB from transcription sites. IκBα was shown experimentally to form a transient ternary complex with DNA-bound NFκB, but the mechanism by which the IκBα accelerates dissociation of the NFκB from the DNA was unknown. In this paper...

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Autores principales: Potoyan, D.A., Zheng, W., Ferreiro, D.U., Wolynes, P.G., Komives, E.A.
Formato: JOUR
Materias:
Bins
Free energy
Transcription
Binary complexes
DNA transcriptions
N-terminal domains
Negative charge
Negatively charged
Positively charged
Specific interaction
Ternary complex
DNA
I kappa B kinase alpha
immunoglobulin enhancer binding protein
chemistry
computer simulation
genetic transcription
metabolism
molecular model
protein domain
Computer Simulation
Models, Molecular
NF-kappa B
NF-KappaB Inhibitor alpha
Protein Domains
Transcription, Genetic
Acceso en línea:http://hdl.handle.net/20.500.12110/paper_15206106_v120_n33_p8532_Potoyan
Aporte de:
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) de Universidad de Buenos Aires
id todo:paper_15206106_v120_n33_p8532_Potoyan
record_format dspace
spelling todo:paper_15206106_v120_n33_p8532_Potoyan2023-10-03T16:20:30Z PEST Control of Molecular Stripping of NFκB from DNA Transcription Sites Potoyan, D.A. Zheng, W. Ferreiro, D.U. Wolynes, P.G. Komives, E.A. Bins Free energy Transcription Binary complexes DNA transcriptions N-terminal domains Negative charge Negatively charged Positively charged Specific interaction Ternary complex DNA DNA I kappa B kinase alpha immunoglobulin enhancer binding protein chemistry computer simulation genetic transcription metabolism molecular model protein domain Computer Simulation DNA Models, Molecular NF-kappa B NF-KappaB Inhibitor alpha Protein Domains Transcription, Genetic We recently proposed a model for IκBα-mediated molecular stripping of NFκB from transcription sites. IκBα was shown experimentally to form a transient ternary complex with DNA-bound NFκB, but the mechanism by which the IκBα accelerates dissociation of the NFκB from the DNA was unknown. In this paper we construct and compute free energy profiles for the wild-type IκBα-mediated molecular stripping reaction of NFκB from DNA and compare with that for a mutant of IκBα bearing a charge-neutralized PEST. The differences in the free energy profile for stripping originate from the frustrated electrostatic interactions between the negatively charged PEST and the DNA. The PEST occupies two different conformations in the NFκB-IκBα binary complex, one of which occupies the DNA-binding cavity. Specific interactions with positively charged residues in the N-terminal domains of both p50 and p65 apparently draw the domains closer together hindering reassociation of DNA. Comparison with the charge-neutralized mutant reveals that all of these functional consequences result from the negative charges in the PEST sequence of IκBα. © 2016 American Chemical Society. Fil:Ferreiro, D.U. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. JOUR info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar http://hdl.handle.net/20.500.12110/paper_15206106_v120_n33_p8532_Potoyan
institution Universidad de Buenos Aires
institution_str I-28
repository_str R-134
collection Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA)
topic Bins
Free energy
Transcription
Binary complexes
DNA transcriptions
N-terminal domains
Negative charge
Negatively charged
Positively charged
Specific interaction
Ternary complex
DNA
DNA
I kappa B kinase alpha
immunoglobulin enhancer binding protein
chemistry
computer simulation
genetic transcription
metabolism
molecular model
protein domain
Computer Simulation
DNA
Models, Molecular
NF-kappa B
NF-KappaB Inhibitor alpha
Protein Domains
Transcription, Genetic
spellingShingle Bins
Free energy
Transcription
Binary complexes
DNA transcriptions
N-terminal domains
Negative charge
Negatively charged
Positively charged
Specific interaction
Ternary complex
DNA
DNA
I kappa B kinase alpha
immunoglobulin enhancer binding protein
chemistry
computer simulation
genetic transcription
metabolism
molecular model
protein domain
Computer Simulation
DNA
Models, Molecular
NF-kappa B
NF-KappaB Inhibitor alpha
Protein Domains
Transcription, Genetic
Potoyan, D.A.
Zheng, W.
Ferreiro, D.U.
Wolynes, P.G.
Komives, E.A.
PEST Control of Molecular Stripping of NFκB from DNA Transcription Sites
topic_facet Bins
Free energy
Transcription
Binary complexes
DNA transcriptions
N-terminal domains
Negative charge
Negatively charged
Positively charged
Specific interaction
Ternary complex
DNA
DNA
I kappa B kinase alpha
immunoglobulin enhancer binding protein
chemistry
computer simulation
genetic transcription
metabolism
molecular model
protein domain
Computer Simulation
DNA
Models, Molecular
NF-kappa B
NF-KappaB Inhibitor alpha
Protein Domains
Transcription, Genetic
description We recently proposed a model for IκBα-mediated molecular stripping of NFκB from transcription sites. IκBα was shown experimentally to form a transient ternary complex with DNA-bound NFκB, but the mechanism by which the IκBα accelerates dissociation of the NFκB from the DNA was unknown. In this paper we construct and compute free energy profiles for the wild-type IκBα-mediated molecular stripping reaction of NFκB from DNA and compare with that for a mutant of IκBα bearing a charge-neutralized PEST. The differences in the free energy profile for stripping originate from the frustrated electrostatic interactions between the negatively charged PEST and the DNA. The PEST occupies two different conformations in the NFκB-IκBα binary complex, one of which occupies the DNA-binding cavity. Specific interactions with positively charged residues in the N-terminal domains of both p50 and p65 apparently draw the domains closer together hindering reassociation of DNA. Comparison with the charge-neutralized mutant reveals that all of these functional consequences result from the negative charges in the PEST sequence of IκBα. © 2016 American Chemical Society.
format JOUR
author Potoyan, D.A.
Zheng, W.
Ferreiro, D.U.
Wolynes, P.G.
Komives, E.A.
author_facet Potoyan, D.A.
Zheng, W.
Ferreiro, D.U.
Wolynes, P.G.
Komives, E.A.
author_sort Potoyan, D.A.
title PEST Control of Molecular Stripping of NFκB from DNA Transcription Sites
title_short PEST Control of Molecular Stripping of NFκB from DNA Transcription Sites
title_full PEST Control of Molecular Stripping of NFκB from DNA Transcription Sites
title_fullStr PEST Control of Molecular Stripping of NFκB from DNA Transcription Sites
title_full_unstemmed PEST Control of Molecular Stripping of NFκB from DNA Transcription Sites
title_sort pest control of molecular stripping of nfκb from dna transcription sites
url http://hdl.handle.net/20.500.12110/paper_15206106_v120_n33_p8532_Potoyan
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AT zhengw pestcontrolofmolecularstrippingofnfkbfromdnatranscriptionsites
AT ferreirodu pestcontrolofmolecularstrippingofnfkbfromdnatranscriptionsites
AT wolynespg pestcontrolofmolecularstrippingofnfkbfromdnatranscriptionsites
AT komivesea pestcontrolofmolecularstrippingofnfkbfromdnatranscriptionsites
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