Protein disulfide isomerases from C-elegans are equally efficient at thiol-disulfide exchange in simple peptide-based systems but show differences in reactivity towards protein substrates

Although the formation of disulfide bonds is an essential process in every living organism, only little is known about the mechanisms in multicellular eukaryotic systems. The reason for this uncertainty is that in addition to the well-known key enzyme protein disulfide isomerase (PDI), several PDI-like proteins are present in the ER of metazoans. In total, there are now 18 PDI-family members in the human endoplasmic reticulum, with different domain architectures and active site chemistries. To understand why multicellular organisms express multiple proteins with similarity to the archetypal mammalian PDI, the properties of three PDIs from the nematode C.elegans were investigated. Here the authors demonstrate that PDI-1, PDI-2, and PDI-3 show comparable kinetic properties in catalyzing thiol:disulfide exchange reactions in two simple peptide-based assays. However, the three enzymes exhibited clear differences in their reactivity towards protein substrates. The authors therefore propose that the three PDIs can catalyze similar thiol-disulfide exchange reactions in a substrate, but due to differences in substrate binding, they can direct a folding polypeptide chain onto different folding pathways and hence fulfil distinct and different functions in the organism