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J Mol Biol. 2017 Apr 7;429(7):999-1008. doi: 10.1016/j.jmb.2017.02.017. Epub 2017 Feb 27.

DNA and IκBα Both Induce Long-Range Conformational Changes in NFκB.

Author information

1
Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92092-0378, USA.
2
Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92092-0378, USA. Electronic address: ekomives@ucsd.edu.

Abstract

We recently discovered that IκBα enhances the rate of release of nuclear factor kappa B (NFκB) from DNA target sites in a process we have termed molecular stripping. Coarse-grained molecular dynamics simulations of the stripping pathway revealed two mechanisms for the enhanced release rate: the negatively charged PEST region of IκBα electrostatically repels the DNA, and the binding of IκBα appears to twist the NFκB heterodimer so that the DNA can no longer bind. Here, we report amide hydrogen/deuterium exchange data that reveal long-range allosteric changes in the NFκB (RelA-p50) heterodimer induced by DNA or IκBα binding. The data suggest that the two Ig-like subdomains of each Rel-homology region, which are connected by a flexible linker in the heterodimer, communicate in such a way that when DNA binds to the N-terminal DNA-binding domains, the nuclear localization signal becomes more highly exchanging. Conversely, when IκBα binds to the dimerization domains, amide exchange throughout the DNA-binding domains is decreased as if the entire domain is becoming globally stabilized. The results help understand how the subtle mechanism of molecular stripping actually occurs.

KEYWORDS:

IκB kinase; Rel homology domain; allostery; amide hydrogen/deuterium exchange; transcription regulation

PMID:
28249778
PMCID:
PMC5389416
DOI:
10.1016/j.jmb.2017.02.017
[Indexed for MEDLINE]
Free PMC Article

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