Protein disulfide-isomerase

Protein disulfide-isomerase has two catalytic thioredoxin-like domains (active sites), each containing the canonical CGHC motif, and two non catalytic domains.^[4][5][6] This structure is similar to the structure of enzymes responsible for oxidative folding in the intermembrane space of the mitochondria; an example of this is mitochondrial IMS import and assembly (Mia40), which has 2 catalytic domains that contain a CX₉C, which is similar to the CGHC domain of PDI.^[7] Bacterial DsbA, responsible for oxidative folding, also has a thioredoxin CXXC domain.^[8]

Function

Protein folding

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]

Regular oxidative folding mechanism and pathway

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]

Misfolded protein mechanism

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.

Redox signaling

In the

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

Insulin turbidity assay: protein disulfide-isomerase 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 protein disulfide-isomerase activity.^[15] Sensitivity of this assay is in micromolar range.

ScRNase assay: protein disulfide-isomerase converts scrambled (inactive)

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]

Members

References