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

Apart from EGF-like domains, disulfide pattern perturbation by uneven numbers of cysteines was also linked to several other extracellular domains in tandem arrangements. The low-density lipoprotein receptor (LDLR) contains a tandem array of LDL-receptor domains and EGF-like domains. LDL-receptor domains are responsible for ligand binding, and EGF-like domains are involved in the degradation and recycling of the receptor. Both types of structural modules are common sites for Cys altering mutations, causing familial hypercholesterolemia [59] . Tumor necrosis factor receptor superfamily member 1A (TNFRSF1A) does not contain EGF-like domains, but its extracellular region is composed of four repeats of the TNFR domain, each stabilized by three disulfide bonds. TNRF can harbor Cys-abolishing mutations, disrupting highly conserved intrachain disulfide bonds, leading to the autoimmune disease periodic syndrome phenotypes. This perturbation could contribute to ligand-independent and enhanced liganddependent tumor necrosis factor receptor signaling under oxidative stress [60] , although impaired cytokine receptor clearance was also proposed as a disease mechanism [61] .