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 disulfide-favoring oxidizing conditions are not only present in the extracellular space, but can also be found in the intermembrane space of the mitochondria. In the light of our knowledge of redox-sensitive conditionally disordered regions located in this compartment, COA6 provides an interesting case as regards disease mutations. The protein is involved in the maturation of the mitochondrial respiratory chain complex, and is critical for biogenesis of mtDNA-encoded COX2. A pathogenic mutation in COA6, leading to substitution of a conserved tryptophan for a cysteine residue, results in a loss of complex IV activity and cardiomyopathy. Towards understanding the molecular basis of pathogenesis, it was recently shown that the human COA6 (p.W59C) mutant leads to an increased aggregation state or mislocalization to the mitochondrial matrix [65, 66] . In agreement with these observations, the observed mutations introduce a redox-sensitive region, which is not predicted in the native protein sequence.