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

Altogether, these results reinforce the importance of redox regulation in key biological processes. However, the analysis of human genetic variation also highlights that mutation of cysteine residues critical for such regulation are correlated with different pathologies (Table 2 ). This analysis shows that such disease-related mutations are found in proteins with different functions and different cellular localization. It is tempting to speculate, that some of these proteins might be involved in sensing or maintaining redox homeostasis in the related organelles. However, the understanding of the structural mechanisms underlying the development of these diseases have already served with potential therapeutic options. CADASIL commonly arises via NOTCH3 cysteine mutations, and artificially introduced exonskipping removes the affected EGF-like domains, and can restore receptor functionality in vitro [90] . The large scale identification of similar redox-sensitive protein regions, together with pathway/mutation analysis can serve as new targets for therapeutic intervention. In addition to endogenous modulations leading to diseases, RSCDPs and redox regulation play critical roles in host-pathogen interactions as well. The role of redox-sensitive proteins in interactions between viruses and eukaryotic hosts is known for several examples, such as Hepatitis C virus [91] , coxsackievirus B3 [92] and Epstein-Barr virus [93] . Viruses, in general, exploit the redoxstate dependence of several signaling pathways of the host cell, and this has even been recognized as having therapeutic value [94] . Our results suggest that the use of redox-state dependent proteins can be a generic theme among viruses targeting multicellular hosts. Redox-state modulation is an emerging theme in the host-pathogen interactions of single-cell eukaryotic pathogens, such as trypanosoma, leishmania, malaria and others. Parasite survival and its successful proliferation depends on the capacity of the invading parasite to cope with the oxidation blast of the host immune system. Therefore an effective redox regulation mechanism is a crucial component for parasite survival which is found and characterized for many unicellular pathogens, including T. congolense and P. falciparum. Our analysis suggests that these pathogens contain significantly large fractions of proteins with redox-sensitive intrinsically disordered regions ( Figure 3A ). Further analysis of these proteins might have therapeutic advances. In order to choose potential candidates for experimental analysis, our method can be coupled with the recently developed experimental tools, which enable real-time mapping of redox states in the parasite [95] .