Large-scale analysis of redox-sensitive conditionally disordered protein regions reveal their widespread nature and key roles in high-level eukaryotic processes

Gábor Erdos; Bálint Mészáros; Dana Reichmann; Zsuzsanna Dosztányi

Cells constantly encounter changes in oxidative conditions which could be a source of signaling information or can evoke significant stress for the organisms. In order to adequately respond, cells have developed various mechanisms that potentially affect a wide range of physiological processes. Many of these responses are centered around the unique chemical and physical properties of cysteine [83] . Due to its tunable reactivity, cysteine residues are exploited in several different types of proteins including enzymes, signaling proteins, chaperones, and others for regulating their activity. A wide repertoire of potential reversible post-translational modifications of thiol groups enables diverse modes of functional regulation and response to a wide spectrum of physiological oxidants and conditions. Another important property of this residue is its high affinity for metal binding and ability to form disulfide bonds, which provide important additional stabilization for different types of protein structures. As the various functions are often dependent on oxidative conditions, cysteine residues can serve as redox-regulated cellular switches modulating the biological activity of various proteins. It has been demonstrated in the case of a growing number of examples the such thiol switches may trigger conformational changes in proteins, and undergo a disorder-to-order (or order-to-disorder) transition upon changes in cellular redox conditions. Unfortunately, a discovery of such thiol switches encoded in conditionally disordered proteins in the large-scale level is challenging and time-consuming. Therefore, a bioinformatic tool which points to the potential redox-regulated intrinsically disordered region can significantly speed up a discovery of such important regions in a proteome level, pointing on potentially interesting targets for the further biochemical characterization. Here, we have developed and applied such a tool implemented in the IUPred2A web server [21] to uncover potential redox-regulated conditionally disordered protein regions at the proteome level. This opens up a way to assess the functional link between redoxregulated processes and the structural dynamics of the proteins involved.