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

The performance of our prediction method is illustrated through three interesting cases. One of the best characterized examples include the Hsp33 heat shock protein from E. coli. This protein chaperone forms a well-defined structure under reducing conditions with the N-terminal domain in close contact with the adjacent linker region and Zn 2+ binding C-terminal domain [27] . However, substrate binding is inaccessible in this conformation and consequently, the protein lacks chaperone activity [13] . Oxidative unfolding (oxidation coupled with mild protein destabilization conditions) causes the C-terminal region to release the Zn 2+ ions, inducing the unfolding of the C-terminal domain together with the adjacent linker region. This transition exposes the substrate binding sites that makes the protein active [28, 29] . The critical region for redox-sensing is located between resides 230 and 266, which contains the four highly conserved cysteine residues that coordinate the Zn 2+ ion under reducing conditions, but form short-range disulfide bonds under oxidative conditions. The large part of the experimentally determined redox-sensitive region is correctly identified by IUPred2A ( Figure 1 ) [30, 31] .