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

Disulfide bond pattern perturbation can also affect individual extracellular domains. The Ret receptor tyrosine kinase receptor is mutated in the extracellular juxtamembrane cysteine-rich . CC-BY-NC 4.0 International license is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the author/funder. It . https://doi.org/10.1101/412692 doi: bioRxiv preprint domain. Similarly to NOTCH3, these mutations induce intermolecular interactions between receptor molecules. The increased dimerization of Ret proteins leads to increased levels of autophosphorylation and tyrosine kinase activity [62, 63] , underlying a frequent form of medullary thyroid cancer (Ret-MEN2A). Furthermore, cysteine modulating mutations can also severely affect single domain extracellular proteins. A prime example is the arginine vasopressinneurophysin II (AVP-NPII), which is composed of a single domain, stabilized by a network of seven disulfide bonds. Both the creation or the abolishment of a Cys residue are likely to alter the three-dimensional structure of the prohormone, which accumulates in the cell body, ultimately leading to neuronal degeneration and hormonal deficit [64] , resulting in autosomal dominant familial neurohypophyseal diabetes insipidus (adFNDI).