Molecular Mechanisms of System Control of NF-kappa B Signaling by I kappa B alpha

作者：Ferreiro Diego U; Komives Elizabeth A^*

来源：Biochemistry, 2010, 49(8): 1560-1567.

DOI：10.1021/bi901948j

The NF-kappa B family of transcription factors responds to inflammatory cytokines with rapid transcriptional activation and subsequent signal repression. Much of the system control depends oil the unique characteristics of its major inhibitor, I kappa B alpha, which appears to have Folding dynamics that underlie the biophysical properties of its activity. Theoretical folding Studies followed by experiments have shown that a portion of the ankyrin repeat domain of I kappa B alpha folds on binding. In resting cells, I kappa B alpha is constantly being synthesized, but most of it is rapidly degraded, leaving only a very small pool of free I kappa B alpha. Nearly all of the NF-kappa B is bound to I kappa B alpha, resulting in near-complete inhibition of nuclear localization and transcriptional activation. Combined solution biophysical measurements and quantitative protein half-life measurements inside cells have allowed us to understand how the inhibition occurs, why I kappa B alpha call be degraded quickly in the free state but remain extremely stable in the bound state, and how signal activation and repression can be tuned by I kappa B folding dynamics. This review summarizes results of in vitro and in vivo experiments that converge demonstrating the effective Interplay between biophysics and cell biology in understanding transcriptional control by the NF-kappa B signaling module.