|PDB structures||RCSB PDB PDBe PDBsum|
|Gene Ontology||AmiGO / EGO|
|protein disulfide isomerase family A, member 2|
|Locus||Chr. 16 p13.3|
|protein disulfide isomerase family A, member 3|
|Locus||Chr. 15 q15|
|protein disulfide isomerase family A, member 4|
|Locus||Chr. 7 q35|
|protein disulfide isomerase family A, member 5|
|Locus||Chr. 3 q21.1|
|protein disulfide isomerase family A, member 6|
|Locus||Chr. 2 p25.1|
Protein disulfide isomerase or PDI is an enzyme in the endoplasmic reticulum in eukaryotes that catalyzes the formation and breakage of disulfide bonds between cysteine residues within proteins as they fold. This allows proteins to quickly find the correct arrangement of disulfide bonds in their fully folded state, and therefore the enzyme acts to catalyze protein folding.
PDI contains four thioredoxin-like domains, two of which retain the canonical CXXC motif. The reduced (dithiol) form of PDI is able to catalyse a reduction of mispaired thiol residues of a particular substrate, acting as an isomerase. Therefore, PDI is capable of catalyzing the post-translational modification disulfide exchange. Such exchange reactions can occur intramolecularly, leading to the rearrangement of disulfide bonds in a single protein.
Another major function of PDI relates to its activity as a chaperone; i.e., it aids wrongly folded proteins to reach a correctly folded state without the aid of enzymatic disulfide shuffling.
Oxidized PDI can catalyze the formation of a disulfide bridge. This reduces PDI, which is re-oxidized by a protein called Ero1.
In the chloroplasts of the unicellular algae Chlamydomonas reinhardtii the PDI RB60 serves as a redox sensor component of an mRNA-binding protein complex implicated in the photo-regulation of the translation of psbA, the RNA encoding for the photosystem II core protein D1. PDI has also been suggested to play a role in the formation of regulatory disulfide bonds in chloroplasts.
PDI has been found to be involved in the breaking of bonds on the HIV gp120 protein during HIV infection of CD4 positive cells, and is required for HIV infection of lymphocytes and monocytes. Some studies have shown it to be available for HIV infection on the surface of the cell clustered around the CD4 protein. Yet conflicting studies have shown that it is not available on the cell surface, but instead is found in significant amounts in the blood plasma.
Assays used for PDI activity
Insulin Turbidity Assay: PDI breaks the two disulfide bonds between two insulin (a and b) chains that results in precipitation of b chain. This precipitation can be monitored at 650 nm, which is indirectly used to monitor PDI activity. Sensitivity of this assay is in micromolar range.
Di-E-GSSG assay: This is the fluorometric assay that can detect picomolar quantities of PDI and therefore is the most sensitive assay to date for detecting PDI activity. Di-E-GSSG has two eosin molecules attached to oxidized glutathione (GSSG). The proximity of eosin molecules leads to the quenching of its fluorescence. However, upon breakage of disulfide bond by PDI, fluorescence increases 70-fold.
Due to the role of PDI in a number of disease states, small molecule inhibitors of PDI have been developed. These molecules can either target the active site of PDI irreversibly  or reversibly.
- Wilkinson B, Gilbert HF (Jun 2004). "Protein disulfide isomerase". Biochimica Et Biophysica Acta 1699 (1-2): 35–44. doi:10.1016/j.bbapap.2004.02.017. PMID 15158710.
- Gruber CW, Cemazar M, Heras B, Martin JL, Craik DJ (Aug 2006). "Protein disulfide isomerase: the structure of oxidative folding". Trends in Biochemical Sciences 31 (8): 455–64. doi:10.1016/j.tibs.2006.06.001. PMID 16815710.
- Galligan JJ, Petersen DR (July 2012). "The human protein disulfide isomerase gene family". Human Genomics 6 (6). doi:10.1186/1479-7364-6-6. PMC 3500226. PMID 23245351.
- Hatahet F, Ruddock LW (Oct 2007). "Substrate recognition by the protein disulfide isomerases". The FEBS Journal 274 (20): 5223–34. doi:10.1111/j.1742-4658.2007.06058.x. PMID 17892489.
- Hatahet F, Ruddock LW (Nov 2009). "Protein disulfide isomerase: a critical evaluation of its function in disulfide bond formation". Antioxidants & Redox Signaling 11 (11): 2807–50. doi:10.1089/ars.2009.2466.x. PMID 19476414.
- Wittenberg G, Danon A (2008). "Disulfide bond formation in chloroplasts". Plant Science 175 (4): 459–466. doi:10.1016/j.plantsci.2008.05.011.
- Ryser HJ, Flückiger R (Aug 2005). "Progress in targeting HIV-1 entry". Drug Discovery Today 10 (16). doi:10.1016/S1359-6446(05)03550-6. PMID 16182193.
- Lundström J, Holmgren A (Jun 1990). "Protein disulfide-isomerase is a substrate for thioredoxin reductase and has thioredoxin-like activity". The Journal of Biological Chemistry 265 (16): 9114–20. PMID 2188973.
- Lyles MM, Gilbert HF (Jan 1991). "Catalysis of the oxidative folding of ribonuclease A by protein disulfide isomerase: dependence of the rate on the composition of the redox buffer". Biochemistry 30 (3): 613–9. doi:10.1021/bi00217a004. PMID 1988050.
- Raturi A, Mutus B (Jul 2007). "Characterization of redox state and reductase activity of protein disulfide isomerase under different redox environments using a sensitive fluorescent assay". Free Radical Biology & Medicine 43 (1): 62–70. doi:10.1016/j.freeradbiomed.2007.03.025. PMID 17561094.
- Hoffstrom, B.G., Kaplan, A., Letso, R., Schmid, R.S. Turmel, G.J. Lo, D. C., Stockwell B.R., "Inhibitors of protein disulfide isomerase suppress apoptosis induced by misfolded proteins" Nat. Chem. Biol. 2010, 6,doi:10.1038/nchembio.467
- Kaplan, A., Gaschler, M.M., Dunn, D.E., Colligan, R., Brown, L. M., Palmer, A.G., Lo, D.C., Stockwell, B.R., "Small molecule induced oxidation of protein disulfide isomerase is neuroprotective" PNAS 2015, doi:10.1073/pnas.1500439112
- Ellgaard L, Ruddock LW (Jan 2005). "The human protein disulphide isomerase family: substrate interactions and functional properties". EMBO Reports 6 (1): 28–32. doi:10.1038/sj.embor.7400311. PMC 1299221. PMID 15643448.
- Appenzeller-Herzog C, Ellgaard L (Apr 2008). "The human PDI family: versatility packed into a single fold". Biochimica Et Biophysica Acta 1783 (4): 535–48. doi:10.1016/j.bbamcr.2007.11.010. PMID 18093543.