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 structural effect of cysteine modifying mutations shows a clear correlation with the subcellular localization of the affected protein. Extracellular regions are targeted through cysteines involved in the formation of the stabilizing disulfide bond patterns, while intracellular proteins are targeted through modulation of metal ion binding ( Table 2) . Extracellular disulfide patterns can be disrupted by both the introduction and elimination of a cysteine, as both lead to an uneven number of cysteines, resulting in incorrect intra-or intermolecular bond formation. The native disulfide patterns are typically highly conserved [50] and apart from their direct enthalpic contribution, they also contribute to protein stability and folding through indirect effects [51] . Mutations of such cysteines typically reduce the stability of the implicated domains, resulting in incorrect folding, or promoting aggregation, which affects several human plasma membrane receptors and extracellular proteins.