Conformational changes in redox pairs of protein structures

Abstract

Disulfides are conventionally viewed as structurally stabilizing elements in proteins but emerging evidence suggests two disulfide subproteomes exist. One group mediates the well known role of structural stabilization. A second redox-active group are best known for their catalytic functions but are increasingly being recognized for their roles in regulation of protein function. Redox-active disulfides are, by their very nature, more susceptible to reduction than structural disulfides; and conversely, the Cys pairs that form them are more susceptible to oxidation. In this study, we searched for potentially redox-active Cys Pairs by scanning the Protein Data Bank for structures of proteins in alternate redox states. The PDB contains over 1134 unique redox pairs of proteins, many of which exhibit conformational differences between alternate redox states. Several classes of structural changes were observed, proteins that exhibit: disulfide oxidation following expulsion of metals such as zinc; major reorganisation of the polypeptide backbone in association with disulfide redox-activity; order/disorder transitions; and changes in quaternary structure. Based on evidence gathered supporting disulfide redox activity, we propose disulfides present in alternate redox states are likely to have physiologically relevant redox activity.

Oxidation state of the XRCC1 N-terminal domain regulates DNA polymerase β binding affinity

“…The importance of reversible disulfide bond formation as a central feature of redox regulation is increasingly recognized (15,(19)(20)(21)(22)(23)(24). We have verified the predicted enhancement in Pol β binding affinity using a fluorescence binding assay and a stabilized analog of oxidized XRCC1-NTD.…”

Structural and biochemical characterization of GTP cyclohydrolase II from Helicobacter pylori reveals its redox dependent catalytic activity

“…However, recent studies reveal that number of bacterial proteins have been identified that seems to be regulated by change in the redox of the cytosol enabling them to survive in ROS environment (Takahashi, 2012;van der Heijden et al, 2014;Vatansever et al, 2013;Wang et al, 2012). Reports are available where proteins containing catalytic zinc sites are redox regulated and exist in both oxidized and reduced forms (Castro et al, 2008;Fan et al, 2009;Fig. 8 (continued) Lowther et al, 2000;Wouters et al, 2010).…”

“…Proteins that form disulfide bonds following expulsion of metals such as Zn 2+ are shown to be redox regulated (Fan et al, 2009;Wouters et al, 2010). Earlier reports indicate that the Zn 2+ dependent enzymes are prone to oxidative inactivation followed by loss of Zn 2+ (Castro et al, 2008;Evans et al, 2002;Fan et al, 2009;Janda et al, 2004;Miller et al, 2005) and reductive reactivation by reducing agents in the presence of zinc chloride (ZnCl 2 ) (Castro et al, 2008;Evans et al, 2002;Lowther et al, 2000;Miller et al, 2005;Qiu et al, 1994).…”

“…Earlier reports indicate that the Zn 2+ dependent enzymes are prone to oxidative inactivation followed by loss of Zn 2+ (Castro et al, 2008;Evans et al, 2002;Fan et al, 2009;Janda et al, 2004;Miller et al, 2005) and reductive reactivation by reducing agents in the presence of zinc chloride (ZnCl 2 ) (Castro et al, 2008;Evans et al, 2002;Lowther et al, 2000;Miller et al, 2005;Qiu et al, 1994). Since, hGCHII was observed in oxidized form with loss of Zn 2+ in the crystal structure and existed in reduced form in solution, we explored whether catalytic activity of hGCHII could be regulated by its redox environment.…”

Activation of Extracellular Transglutaminase 2 by Mechanical Force in the Arterial Wall

“…Generally, these latter redox-active disulfides have high redox potentials, ranging from -120 to -270 mV, in contrast to structural disulfides, whose redox potential can be as low as -470 mV [65]. This property makes the former bonds more prone to be reduced, and also makes the Cys pairs that form them more susceptible to oxidation [65]. In this way, these active disulfide bridges act as highly sensitive redox switches for the regulation of protein function, which might be achievable by altering protein conformation.…”