A Disorder-Induced Domino-Like Destabilization Mechanism Governs the Folding and Functional Dynamics of the Repeat Protein IκBα

Srinivasan Sivanandan, Athi N. Naganathan

Abstract: Author Summary It is well recognized that unstructured or disordered proteins play a vital role in the cell. How does this disorder translate into function, and what effect does it have when linked to ordered regions? We attempt to answer this question by computationally characterizing the repeat protein IκBα, a central player in the NF-κB signaling module that possesses both structured and disordered domains. Upon constraining a structure-based statistical mechanical model with equilibrium experiments, we are able to successfully predict both the ensemble kinetic and single-molecule behaviors. Functionally, we unearth a unique mechanism in which the effect of disorder propagates, even into ordered regions, in a domino-like fashion, thus rendering the entire structure highly flexible. In other words, the evolutionarily designed disorder in IκBα places it on a functional precipice that can be either recruited for binding to transduce external stimuli or just be degraded to shut down the inhibitory effect, reconciling both functional and folding behaviors in a single framework.