PDI

Related Reading

Introduction

Protein disulfide isomerase (PDI) is the first folding catalyst isolated from rat liver. It is distributed in many tissues and accounts for 0.8% of total cell protein. PDI is an important cellular defense against general protein misfolding. In addition, it is also responsible for the isomerization, formation, and rearrangement of protein disulfide bonds, thereby providing another mechanism for maintaining the native protein conformation. Disulfide bonds play an essential role in the folding and stability of proteins. Most cell compartments are in a reducing environment, so protein disulfide bonds are usually unstable in the cytosol. PDI contributes to the folding of redox proteins, as well as multiple intramolecular thiol-disulfide exchange and isomerization (reduction) activities, and it has a high specificity in its interaction with different substrates. Although PDI is believed to resident mainly in the ER, it has also been found on the cell surface, cytoplasm, mitochondria, and extracellular matrix. At present, the mechanism by which PDI escapes from ER is still unclear. In addition, cell surface PDIs identified in hepatocytes, platelets and endothelial cells have been reported to have specific functions.

Structure and Superfamily of PDI

The full-length PDI contains 508 amino acids and consists of four domains: a, b, b', and a'. The a and a' domains share 47% similarity and both contain the active site CGHC. The b and b' domains are 28% identical, which facilitates the binding of protein substrates. PDI also contains an x-linker region and a C-terminus containing the KDEL-ER retrieval sequence. So far, the structural data of yeast PDI has been obtained, revealing that it adopts a U-shaped structure with a and a' domains facing each other. Although the three-dimensional structure of human PDI is still under investigation, the structure of each single thioredoxin domain and the domain combination bb'c and bb'cxac have been determined.

Figure 1. Domain structure of PDI (Parakh, S.; Atkin, J.D. 2015)

Summary

PDI plays an important role in various diseases due to its multiple biological functions, versatile redox behaviors, and interaction with other proteins. However, there are still many unresolved issues, especially the role of PDI in non-ER subcellular locations, and the substrate specificity of PDI family members. In future research, before fully understanding the normal cellular functions of PDI, it is necessary to replicate the precise functions of PDI in the ER and other cellular locations. Up-regulation of PDI is a cellular defense mechanism that restores proteostasis. However, due to abnormal post-translational modifications, the functional properties of PDI may be abolished, which plays an important role in neurodegenerative diseases involving the destruction of redox regulation. Recent studies have shown that PDI is a trigger for cell apoptosis, especially related to the accumulation of misfolded proteins. However, in response to an unknown trigger, PDI subsequently undergoes apoptosis when protein homeostasis cannot be resolved. Therefore, abnormal post-translational modifications and the pro-apoptotic function of PDI can further aggravate the adverse effects of PDI.

Figure 2. Schematic diagram outlining the dual nature of PDI, focusing on neurodegenerative disorders as an example (Parakh, S.; Atkin, J.D. 2015)

In conclusion, PDI is an effective catalyst and protein chaperone. It can catalyze the effective folding of newly synthesized proteins to maintain protein homeostasis and inhibit abnormal protein aggregation. It plays an important role in protein quality control and ERAD. The subcellular location of PDI, the level of endoplasmic reticulum stress, and the redox environment may all affect the protective or harmful functions of PDI. Although further research is needed, many studies have shown that PDI has the potential to be exploited therapeutically in various diseases, but this requires different methods according to different diseases. In neurodegenerative diseases, elevation of the levels of total PDI, so restoring PDI function can reduce protein misfolding, which may be an effective treatment. However, in contrast, reducing PDI levels may be a suitable strategy for the treatment of cancer or cardiovascular disease. Similarly, in neurodegenerative diseases, it is necessary to reduce the level of aberrantly modified PDI, which can defend against the pro-apoptotic properties of PDI.

Figure 3. Schematic diagram illustrating possible therapeutic applications to modulate PDI function (Parakh, S.; Atkin, J.D. 2015)