PEST Control of Molecular Stripping of NFκB from DNA Transcription Sites

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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Guardado en:
Detalles Bibliográficos
Autor principal: Ferreiro, Diego U.
Publicado: 2016
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:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_15206106_v120_n33_p8532_Potoyan
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
Descripción
Sumario: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.

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