For disordered proteins, ligand binding can be a critical event that changes their structural dynamics. The ability to characterize such changes would facilitate the development of drugs designed to stabilize disordered proteins, whose mis-folding is important for a number of pathologies, including neurodegenerative diseases such as Parkinson's and Alzheimer's diseases. In this study, we used hydrogen/deuterium exchange, differential crosslinking, differential surface modification, and molecular dynamics (MD) simulations to characterize the structural changes in disordered proteins that result from ligand binding. We show here that both an ATP-independent protein chaperone, Spy L32P, and the FK506 binding domain of a prolyl isomerase, FKBP-25 F145A/I223P, are disordered, yet exhibit structures that are distinct from chemically denatured unfolded states in solution, and that they undergo transitions to a more structured state upon ligand binding. These systems may serve as models for the characterization of ligand-induced disorder-to-order transitions in proteins using structural proteomics approaches. SIGNIFICANCE: In this study, we used hydrogen/deuterium exchange, differential crosslinking, differential surface modification, and molecular-dynamics simulations to characterize the structural changes in disordered proteins that result from ligand binding. The protein-ligand systems studied here (the ATP-independent protein chaperone, Spy L32P, and the FK506 binding domain of a prolyl isomerase, FKBP-25 F145A/I223P) may serve as models for understanding ligand-induced disorder-to-order transitions in proteins. Additionally, the structural proteomic techniques demonstrated here are shown to be effective tools for the characterization of disorder-to-order transitions and can be used to facilitate study of other systems in which this class of structural transition can be used for modulating major pathological features of disease, such as the abnormal protein aggregation that occurs with Parkinson's disease and Alzheimer's disease.
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| http://dx.doi.org/10.1016/j.jprot.2019.103544 | DOI Listing |
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