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

One of the main outcomes of the presented study is that redox-sensitive conditionally disordered regions (RSCDRs) are widespread in various proteomes, especially in eukaryotic multicellular organisms. According to our predictions, around 5% of the proteome corresponds to proteins with RSCDRs in yeast, however, this proportion increases to nearly 30% in the human proteome. This highly unexpected result gains more credence with the domain-level analysis that established a strong correlation between the increased amount of RSCDRs and the expansion of potentially redox-sensitive domains, such as intracellular zinc fingers or the extracellular EGF domains, at various points of evolution. In yeast, the most common domains predicted to be redox-regulated through conditional disorder are various types of zinc fingers including the DNAJ_C family, or certain subunits of the ribosome. We have used our bioinformatic tool to identify potentially conditionally disordered regions associated with known peroxide-sensitive cysteines in yeast, and identified 15 potentially interesting proteins harboring the RSCDRs (Table 1 ). This subset of proteins includes ribosomal proteins, a mitochondrial cochaperone, YDJ1, and transcriptional regulators TAF1, ELF and RDS3. This analysis supports a very-well established interplay between protein and redox homeostasis in cells (29351842), revealing potential members of the protein homeostasis system that might employ redoxregulated conformational changes to regulate their function during oxidative stress. These predictions might direct further experimental analysis of a crosstalk between redox regulation, structural changes, and proteostasis related function. Interestingly, proteins with the predicted redox-regulated disordered regions are predominant in drosophila species. This increase can be partially attributed to the expansion of the zinc finger families. However, novel domains also appear such as the zinc binding LIM domains, some of which were shown to change their intracellular location upon redox regulation. The functional importance of these domains is further underlined by their involvement in various diseases that alter cysteine residues with a critical role in this type of regulation. Moreover, another large group of predicted RSCDPs corresponds to extracellular domains found only in multicellular organisms. The redox regulation of extracellular proteins could be important for their transfer to the extracellular matrix, and assembly in their target location. Thus, mutations of such critical, redox-regulated cysteine residues can lead to devastating diseases ( Table 2) . Coupling of potentially redox-sensitive thiols and structural plasticity is very well characterized in proteins transferred from cytosol to other organelles, such as mitochondria and peroxisome. Thus, the similar mechanism might be crucial for the biogenesis of extracellular proteins, including receptors. In addition to biogenesis, receptors could utilize redox-regulated regions for sensing changes in redox status and mediate related signaling events [60] [62, 63] . Our results suggest that the human and drosophila proteomes share many common redox-sensitive structural switching domains, corresponding to similar functions. However, the abundance of these domains is further elevated in Homo sapiens, with the most drastic increase observed in the case of the C2H2 type zinc finger domains.