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 most targeted extracellular structural modules in the analyzed dataset are EGF-like domains, which are stabilized via three pairs of cysteines forming three disulfide bonds. EGFlike domains are commonly found in tandem repeats in the ligand binding regions of receptors, and are often targeted by germline mutations. Cys-altering mutations in the EGF domains of fibrillin, the major structural constituent of extracellular microfibrils [52, 53] results in connective tissue disorders such as the Marfan syndrome. The perturbation results in short or long-range structural rearrangements, and can affect the Ca 2+ binding ability of the domain, which can lead to increased susceptibility to proteolysis, retention in the endoplasmic reticulum, and delayed secretion [52] . It has been suggested that increased oxidative stress can contribute to disease progression [54] . A radically different phenotype is produced by EGF Cys mutations of CRB1, linked to various retinal dystrophies. CRB1 has an important role in maintaining retinal integrity, and its mutations result in ROS accumulation and photoreceptor cell death [55] . Similar mutations in NOTCH3 cause the vascular dementia disease Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL). In this case, however, mutations lead to impaired intracellular trafficking and maturation of the mutated Notch 3 receptors [56] , and are not directly related to oxidative stress [57] . In NOTCH3, the uneven number of cysteines likely contributes to intermolecular disulfide bridges, as these mutations increase multimerization and aggregate formation [58] .