Protein disulfide-isomerase

PDI displays oxidoreductase and isomerase properties, both of which depend on the type of substrate that binds to protein disulfide-isomerase and changes in protein disulfide-isomerase's redox state.[4] These types of activities allow for oxidative folding of proteins. Oxidative folding involves the oxidation of reduced cysteine residues of nascent proteins; upon oxidation of these cysteine residues, disulfide bridges are formed, which stabilizes proteins and allows for native structures (namely tertiary and quaternary structures).[4]

PDI is specifically responsible for folding proteins in the ER.[6] In an unfolded protein, a cysteine residue forms a mixed disulfide with a cysteine residue in an active site (CGHC motif) of protein disulfide-isomerase. A second cysteine residue then forms a stable disulfide bridge within the substrate, leaving protein disulfide-isomerase's two active-site cysteine residues in a reduced state.[4]

Afterwards, PDI can be regenerated to its oxidized form in the endoplasmic reticulum by transferring electrons to reoxidizing proteins such ER oxidoreductin 1 (Ero 1), VKOR (vitamin K epoxide reductase), glutathione peroxidase (Gpx7/8), and PrxIV (peroxiredoxin IV).[4][9][10][6] Ero1 is thought to be the main reoxidizing protein of PDI, and the pathway of reoxidation of PDI for Ero1 is more understood than that of other proteins.[10] Ero1 accepts electrons from PDI and donates these electrons to oxygen molecules in the ER, which leads to the formation of hydrogen peroxide.[10]

The reduced (dithiol) form of protein disulfide-isomerase is able to catalyze a reduction of a misformed disulfide bridge of a substrate through either reductase activity or isomerase activity.[11] For the reductase method, a misfolded substrate disulfide bond is converted to a pair of reduced cysteine residues by the transfer of electrons from glutathione and NADPH. Afterwards, normal folding occurs with oxidative disulfide bond formation between the correct pairs of substrate cysteine residues, leading to a properly folded protein. For the isomerase method, intramolecular rearrangement of substrate functional groups is catalyzed near the N terminus of each active site.[4] Therefore, protein disulfide-isomerase is capable of catalyzing the post-translational modification disulfide exchange.

In the chloroplasts of the unicellular algae Chlamydomonas reinhardtii the protein disulfide-isomerase RB60 serves as a redox sensor component of an mRNA-binding protein complex implicated in the photoregulation of the translation of psbA, the RNA encoding for the photosystem II core protein D1. Protein disulfide-isomerase has also been suggested to play a role in the formation of regulatory disulfide bonds in chloroplasts.[12]

Protein disulfide-isomerase helps load antigenic peptides into MHC class I molecules. These molecules (MHC I) are related to the peptide presentation by antigen-presenting cells in the immune response.

Protein disulfide-isomerase 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.[13] 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.

Another major function of protein disulfide-isomerase relates to its activity as a chaperone; its b' domain aids in the binding of misfolded protein for subsequent degradation.[4] This is regulated by three ER membrane proteins, Protein Kinase RNA-like endoplasmic reticulum kinase (PERK), inositol-requiring kinase 1 (IRE1), and activating transcription factor 6 (ATF6).[4][14] They respond to high levels of misfolded proteins in the ER through intracellular signaling cascades that can activate PDI's chaperone activity.[4] These signals can also inactivate translation of these misfolded proteins, because the cascade travels from the ER to the nucleus.[4]

Redox dysregulation leads to increases in nitrosative stress in the endoplasmic reticulum. Such adverse changes in the normal cellular environment of susceptible cells, such as neurons, leads to nonfunctioning thiol-containing enzymes.[14] More specifically, protein disulfide-isomerase can no longer fix misfolded proteins once its thiol group in its active site has a nitric monoxide group attached to it; as a result, accumulation of misfolded proteins occurs in neurons, which has been associated with the development of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease.[4][14]

Due to the role of protein disulfide-isomerase in a number of disease states, small molecule inhibitors of protein disulfide-isomerase have been developed. These molecules can either target the active site of protein disulfide-isomerase irreversibly[18] or reversibly.[19]

It has been shown that protein disulfide-isomerase activity is inhibited by red wine and grape juice, which could be the explanation for the French paradox.[20]