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

In contrast to their extracellular counterparts, disease mutations affecting putative redoxsensitive conditionally disordered regions located in proteins inside the cell target metal ion coordinating domains. The majority of such mutations perturb the Zn 2+ ion binding of various types of zinc finger (ZNF) domains, and in these cases the mutations almost ubiquitously eliminate cysteines. As one of the most common function of ZNF domains is DNA binding, several cysteine-modifying germline mutations affect transcription factors. One of the most well studied such protein is the human zinc-finger transcription factor WT1. WT1 ZNF cysteine mutations result in abnormal development of the genitourinary system and are associated with various diseases including Wilms tumors, Denys-Drash syndrome, Nephrotic syndrome 4 and Meacham syndrome. The four C-terminal tandem ZNFs of WT1 [67] are mutational hotspots, with the majority of the contained mutations altering the zinc coordinating cysteine residues of ZF2 and ZF3 domains. These mutations can increase the flexibility of the protein or alter its DNA-binding specificity [68] . While there is no direct evidence that WT1 is redox-regulated, in the case of the similar protein EGR1 it was shown that the redox state modules the DNA binding activity of the protein [69, 70] . Another transcription factor, PHF6 is involved in chromatin regulation and neural development [71] . Germline mutations connected to the X-linked mental retardation disorder Börjeson-Forssman-Lehmann syndrome eliminate the conserved C45, C99 and C305 cysteines in either the C2HC or the PHD-type zinc finger. These mutations affect the structure core or zinc coordination of the PHF6-ePHD2 domain and destabilize the correct protein fold and consequently interfere with the normal biological function the protein [71] . Apart from direct DNA binding, ZNF targeting mutations can affect transcription in a more indirect way. C1430R and C1471Y mutations in KMT2D likely disrupt the PHD5 finger fold, and reduce histone binding and catalytic activity of the protein [72] , leading to Kabuki syndrome.