Role of disorder in I?B-NF?B interaction

The paradigmatic transcription factors of the NF?B family provide an increasingly complex view of the mechanism of signal-mediated transcriptional activation. Although the primary event, phosphorylation and subsequent ubiquitin-dependent degradation of I?Ba, the inhibitor of the canonical NF?B (p50/p65), is reasonably well understood, the means whereby the activation is turned off by postinduction repression are less well understood. Recent work highlighted in this review suggests that the inhibitor I?Ba participates in the stripping of NF?B from the DNA, and that this process relies heavily on the disordered and weakly ordered segments of I?Ba. Kinetic and equilibrium measurements in vitro as well as genetic screens in vivo convincingly demonstrate not only that I?Ba greatly increases the dissociation rate of NF?B from DNA but also that further control of the process is mediated by the extremely short half-life of free I?Ba, doubtless a result of the overall weakly folded nature of the free protein. These studies illustrate the versatility of protein systems that use not only well-structured proteins and protein complexes but also the full range of available weakly structured and disordered states to maximize functional efficiency and metabolic control. (C) 2012 IUBMB IUBMB Life, 2012