CHAPTER 4.2: Disulfide Bond Formation in the Endoplasmic Reticulum

The formation of disulfides in secretory proteins is a key post-translation modification necessary to support structural stability and functionality. In the mammalian endoplasmic reticulum (ER), correct disulfide formation is accomplished by a number of distinct, tightly regulated mechanisms that constitute the ER oxidative pathways. A central theme of the ER oxidative pathways includes the protein disulfide isomerase (PDI) family of oxidoreductases that catalyse disulfide formation in newly synthesised proteins. Introduction of disulfides by PDIs is an error-prone process that often results in the formation of incorrect disulfides, which requires reduction and isomerisation to the correct disulfides – reactions also catalysed by PDI enzymes. To enable reduction and isomerisation, the PDI active sites have to be reduced. Therefore, ER disulfide formation requires the cooperation of both oxidative and reductive machineries, seemingly opposing pathways that have evolved to work in harmony to ensure efficient oxidative protein folding.