Kinetic enhancement of NF-κB•DNA dissociation by IκBα

A hallmark of the NF-kappa B transcription response to inflammatory cytokines is the remarkably rapid rate of robust activation and subsequent signal repression. Although the rapidity of postinduction repression is explained partly by the fact that the gene for I kappa B alpha is strongly induced by NF-kappa B, the newly synthesized I kappa B alpha still must enter the nucleus and compete for binding to NF-kappa B with the very large number of kappa B sites in the DNA. We present results from real-time binding kinetic experiments, demonstrating that I kappa B alpha increases the dissociation rate of NF-kappa B from the DNA in a highly efficient kinetic process. Analysis of various I kappa B mutant proteins shows that this process requires the C-terminal PEST sequence and the weakly folded fifth and sixth ankyrin repeats of I kappa B alpha. Mutational stabilization of these repeats reduces the efficiency with which I kappa B alpha enhances the dissociation rate.