CHAPTER 3.5: Disulfide Bond Formation Downstream of the Endoplasmic Reticulum

Disulfide bonds are typically introduced into secretory and cell-surface proteins in the endoplasmic reticulum (ER). Nevertheless, instances of disulfide formation are also observed later in the secretory pathway. Sulfhydryl oxidases of the QSOX family catalyze disulfide bond formation downstream of the ER, either in the Golgi apparatus or extracellularly. The difference in pH between the ER and downstream compartments may induce conformational changes in proteins that allow spontaneous disulfide rearrangements or that expose cysteines to sulfhydryl oxidases for enzymatic pairing. Although most cysteines in proteins residing in the secretory pathway or exposed to the extracellular environment become linked in disulfides during protein maturation, certain extracellular proteins contain conserved unpaired cysteines. This fact, coupled with the observed context-specific secretion of redox-active enzymes that normally reside in intracellular compartments, suggests that cysteine redox modifications occur both extra- and intracellularly.