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

Redox regulation is essential for the survival of all organisms, as cells constantly encounter the transient accumulation of reactive oxygen species (ROS). ROS may be generated exogenously or endogenously due to metabolic activity or inflammation, while subsequent oxidative damage can cause widespread protein unfolding and aggregation. It may also contribute to the pathogenesis of many different diseases, as well as to degenerative processes associated with aging. However, ROS can also serve as cellular signaling molecules and regulate various biological processes such as the immune response, cell proliferation, development, and more [8, 9] . The specific effects of ROS are captured in large part through the covalent and reversible modifications of specific cysteine residues, which can in turn modify the structural or functional properties of the redox-sensitive target proteins. Such post-translational modifications are tightly regulated by changes in levels of diverse physiological oxidants and is generally faster than expression of specific regulatory proteins. Over the last decade, numerous examples of such thiol-switch proteins have been uncovered, spanning different functions and regulation modes [6, 7, 10] . The functions of select proteins were found to be regulated by oxidative modifications of a specific cysteine thiol forming either sulfenic (e.g., in 1-Cys peroxiredoxin) or sulfenamide (e.g., in tyrosine phosphatase 1B, leading to regulation of the Ras signaling pathway). Another more studied mode of activation is through disulfide bond formation by redox-sensitive cysteine residues, typically located in close proximity of each other. These disulfide bridges can either promote disorder-to-order transitions (e.g., chloroplast regulator of the calvin cycle, CP12 [11] and cell growth modulator, granulin Grn-3 [12] ) or vice versa (e.g., in the bacterial protein chaperone Hsp33 [13] and mammalian copper chaperone Cox17 [14] ) in response to shifts in the cellular redox status [6] .