Regions of IκBα that are critical for its inhibition of NF-κB·DNA interaction fold upon binding to NF-κB

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Abstract
Nuclear factor κB (NF-κB) transcription factors regulate genes responsible for critical cellular processes. IκBα, -β, and -ε bind to NF-κBs and inhibit their transcriptional activity. The NF-κB-binding domains of IκBs contain six ankyrin repeats (ARs), which adopt a β-hairpin/α-helix/loop/α-helix/loop architecture. IκBα appears compactly folded in the IκBα·NF-κB crystal structure, but biophysical studies suggested that IκBα might be flexible even when bound to NF-κB. Amide H/ 2 H exchange in free IκBα 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-κB-bound IκBα reveals that the β-hairpins in ARs 5 and 6 fold upon binding to NF-κB, but AR 1 remains highly solvent accessible. These regions are implicated in various aspects of NF-κB regulation, such as controlling degradation of IκBα, enabling high-affinity interaction with different NF-κB dimers, and preventing NF-κB from binding to its target DNA. Thus, IκBα conformational flexibility and regions of IκBα folding upon binding to NF-κB are important attributes for its regulation of NF-κB transcriptional activity.

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