Disulfide bonds play an important role in physiology and are the mainstay of proteins that reside in the plasma membrane and of those that are secreted outside the cell. Disulfide-bond-containing proteins comprise ∼30% of all eukaryotic proteins. Using bovine pancreatic ribonuclease A (RNase A) as an exemplar, we review the regeneration (oxidative folding) of disulfide-bond-containing proteins from their fully reduced state to the biologically active form. We discuss the key aspects of the oxidative folding landscape w.r.t. the acquisition and retention of native disulfide bonds which is an essential requirement for the polypeptide to be biologically functional. By re-examining the regeneration trajectory in light of the symbiotic relationship between native disulfide bonds and a protective structure, we describe the elements that compete with the processes that secure native disulfide bonds in disulfide-coupled protein folding. The impact of native-disulfide-bond formation on protein stability, trafficking, protein misfolding, and neurodegenerative onset is elaborated upon.
© 2021 The Author. Published by American Chemical Society.