title: A disorder-induced domino-like destabilization mechanism governs the folding and functional dynamics of the repeat protein IκBα.
abstract: The stability of the repeat protein IκBα, a transcriptional inhibitor in mammalian cells, is critical in the functioning of the NF-κB signaling module implicated in an array of cellular processes, including cell growth, disease, immunity and apoptosis. Structurally, IκBα is complex, with both ordered and disordered regions, thus posing a challenge to the available computational protocols to model its conformational behavior. Here, we introduce a simple procedure to model disorder in systems that undergo binding-induced folding that involves modulation of the contact map guided by equilibrium experimental observables in combination with an Ising-like Wako-Saitô-Muñoz-Eaton model. This one-step procedure alone is able to reproduce a variety of experimental observables, including ensemble thermodynamics (scanning calorimetry, pre-transitions, m-values) and kinetics (roll-over in chevron plot, intermediates and their identity), and is consistent with hydrogen-deuterium exchange measurements. We further capture the intricate distance-dynamics between the domains as measured by single-molecule FRET by combining the model predictions with simple polymer physics arguments. Our results reveal a unique mechanism at work in IκBα folding, wherein disorder in one domain initiates a domino-like effect partially destabilizing neighboring domains, thus highlighting the effect of symmetry-breaking at the level of primary sequences. The offshoot is a multi-state and a dynamic conformational landscape that is populated by increasingly partially folded ensembles upon destabilization. Our results provide, in a straightforward fashion, a rationale to the promiscuous binding and short intracellular half-life of IκBα evolutionarily engineered into it through repeats with variable stabilities and expand the functional repertoire of disordered regions in proteins.
authors.affiliation: Department of Biotechnology, Indian Institute of Technology Kharagpur, Kharagpur, India.
authors.forename: Srinivasan
authors.initials: S
authors.lastname: Sivanandan
authors.affiliation: Department of Biotechnology, Indian Institute of Technology Madras, Chennai, India.
authors.forename: Athi N
authors.initials: AN
authors.lastname: Naganathan
mesh_terms: D020672:I-kappa B Proteins / Q000737:chemistry*; D008958:Models, Molecular; D000072000:NF-KappaB Inhibitor alpha; D017510:Protein Folding; D013816:Thermodynamics
chemical_list: D020672:I-kappa B Proteins; D000072000:NF-KappaB Inhibitor alpha