I?Ba, the most abundant inhibitor protein of the NF-?B transcription factor, has six ankyrin repeats (ARs) in its AR domain: four well-folded ARs (repeats 1 through 4) and two weakly folded ARs (repeats 5 and 6).  The AR 5-6 conformational flexibility is critical for regulating NF-?B signaling. Single-molecule FRET experiments probing the weakly folded region demonstrated that the native state of I?Ba transiently populates an intrinsically disordered state characterized by a more extended structure and slow millisecond-scale fluctuations. Systematic placement of FRET fluorophores along ARs revealed a sequential unfolding of the native state of I?Ba that starts with the C-terminal AR 6 at room temperature, followed by AR 5 at 37 �C.  Fluctuations in the intrinsically disordered AR 5-6 region correspond with the ability of I?Ba to dissociate NF-?B from DNA transcription sites, and could provide the basis for new therapies to numerous diseases.

Nanospring dynamics and sequential unfolding of the IκBα ankyrin repeat domain

243rd National Meeting (2012)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.