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Proc Natl Acad Sci U S A. 2006 Dec 12;103(50):18951-6. Epub 2006 Dec 5.

Regions of IkappaBalpha that are critical for its inhibition of NF-kappaB.DNA interaction fold upon binding to NF-kappaB.

Author information

1
Department of Chemistry and Biochemistry, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0378, USA.

Abstract

Nuclear factor kappaB (NF-kappaB) transcription factors regulate genes responsible for critical cellular processes. IkappaBalpha, -beta, and -epsilon bind to NF-kappaBs and inhibit their transcriptional activity. The NF-kappaB-binding domains of IkappaBs contain six ankyrin repeats (ARs), which adopt a beta-hairpin/alpha-helix/loop/alpha-helix/loop architecture. IkappaBalpha appears compactly folded in the IkappaBalpha.NF-kappaB crystal structure, but biophysical studies suggested that IkappaBalpha might be flexible even when bound to NF-kappaB. Amide H/(2)H exchange in free IkappaBalpha suggests that ARs 2-4 are compact, but ARs 1, 5, and 6 are conformationally flexible. Amide H/(2)H exchange is one of few techniques able to experimentally identify regions that fold upon binding. Comparison of amide H/(2)H exchange in free and NF-kappaB-bound IkappaBalpha reveals that the beta-hairpins in ARs 5 and 6 fold upon binding to NF-kappaB, but AR 1 remains highly solvent accessible. These regions are implicated in various aspects of NF-kappaB regulation, such as controlling degradation of IkappaBalpha, enabling high-affinity interaction with different NF-kappaB dimers, and preventing NF-kappaB from binding to its target DNA. Thus, IkappaBalpha conformational flexibility and regions of IkappaBalpha folding upon binding to NF-kappaB are important attributes for its regulation of NF-kappaB transcriptional activity.

PMID:
17148610
PMCID:
PMC1748158
DOI:
10.1073/pnas.0605794103
[Indexed for MEDLINE]
Free PMC Article

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