Probing Surfaces in Dynamic Protein Interactions.

Emil Spreitzer, Sinem Usluer, Tobias Madl

Journal of molecular biology 2020 Apr 17

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Proteins and their interactions control a plethora of biological functions and enable life. Protein-protein interactions can be highly dynamic, involve proteins with different degrees of "foldedness," and are often regulated through an intricate network of post-translational modifications. Central parts of protein-protein networks are intrinsically disordered proteins (IDPs). IDPs act as regulatory interaction hubs, enabled by their flexible nature. They employ various modes of binding mechanisms, from folding upon ligand binding to formation of highly dynamic "fuzzy" protein-protein complexes. Mutations or perturbations in regulation of IDPs are hallmarks of many diseases. Protein surfaces play key roles in protein-protein interactions. However, protein surfaces and protein surface accessibility are difficult to study experimentally. NMR-based solvent paramagnetic relaxation enhancement (sPRE) can provide quantitative experimental information on protein surface accessibility, which can be further used to obtain distance information for structure determination, identification of interaction surfaces, conformational changes, and identification of low-populated transient structure and long-range contacts in IDPs and dynamic protein-protein interactions. In this review, we present and discuss state-of the art sPRE techniques and their applications to investigate structure and dynamics of IDPs and protein-protein interactions. Finally, we provide an outline for potential future applications of the sPRE approach in combination with complementary techniques and modeling, to study novel paradigms, such as liquid-liquid phase separation, regulation of IDPs and protein-protein interactions by post-translational modifications, and targeting of disordered proteins. Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Citation

Emil Spreitzer, Sinem Usluer, Tobias Madl. Probing Surfaces in Dynamic Protein Interactions. Journal of molecular biology. 2020 Apr 17;432(9):2949-2972