Conformational Transitions Associated with Different Redox States of Di-Thiol Pairs

Abstract

Protein redox regulation is of growing interest because of its relevance to neurodegenerative diseases, cancer, diabetes and heart disease. Redox-active disulfides 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 mining structures of proteins in alternate redox states from the Protein Data Bank. Over 1,134 unique redox pairs of proteins were found, many of which exhibit conformational differences between alternate redox states. Our study is the first to systematically study these conformational changes. Several classes of structural changes were observed, proteins that exhibit: disulfide oxidation following expulsion of metals such as Zn; order/disorder transitions; changes in quaternary structure and major reorganisation of the polypeptide backbone in association with disulfide redox-activity. This latter group, also known as proteins, challenge Anfinsen's thesis of a one-to-one mapping of sequence to structure, also known as the thermodynamic hypothesis. Our study shows the conformational state of morphing proteins can be influenced by redox conditions.