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Protein disulfide isomerase, or PDI, is an enzyme in the endoplasmic reticulum (ER) in eukaryotes and the periplasm of bacteria 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.
Thioredoxin reductases are enzymes that reduce thioredoxin (Trx). Two classes of thioredoxin reductase have been identified: one class in bacteria and some eukaryotes and one in animals. In bacteria TrxR also catalyzes the reduction of glutaredoxin like proteins known as NrdH. Both classes are flavoproteins which function as homodimers. Each monomer contains a FAD prosthetic group, a NADPH binding domain, and an active site containing a redox-active disulfide bond.
Thioredoxin is a class of small redox proteins known to be present in all organisms. It plays a role in many important biological processes, including redox signaling. In humans, thioredoxins are encoded by TXN and TXN2 genes. Loss-of-function mutation of either of the two human thioredoxin genes is lethal at the four-cell stage of the developing embryo. Although not entirely understood, thioredoxin is linked to medicine through their response to reactive oxygen species (ROS). In plants, thioredoxins regulate a spectrum of critical functions, ranging from photosynthesis to growth, flowering and the development and germination of seeds. Thioredoxins play a role in cell-to-cell communication.
Oxidative protein folding is a process that is responsible for the formation of disulfide bonds between cysteine residues in proteins. The driving force behind this process is a redox reaction, in which electrons pass between several proteins and finally to a terminal electron acceptor.
The thioredoxin fold is a protein fold common to enzymes that catalyze disulfide bond formation and isomerization. The fold is named for the canonical example thioredoxin and is found in both prokaryotic and eukaryotic proteins. It is an example of an alpha/beta protein fold that has oxidoreductase activity. The fold's spatial topology consists of a four-stranded antiparallel beta sheet sandwiched between three alpha helices. The strand topology is 2134 with 3 antiparallel to the rest.
ER oxidoreductin 1 (Ero1) is an oxidoreductase enzyme that catalyses the formation and isomerization of protein disulfide bonds in the endoplasmic reticulum (ER) of eukaryotes. ER Oxidoreductin 1 (Ero1) is a conserved, luminal, glycoprotein that is tightly associated with the ER membrane, and is essential for the oxidation of protein dithiols. Since disulfide bond formation is an oxidative process, the major pathway of its catalysis has evolved to utilise oxidoreductases, which become reduced during the thiol-disulfide exchange reactions that oxidise the cysteine thiol groups of nascent polypeptides. Ero1 is required for the introduction of oxidising equivalents into the ER and their direct transfer to protein disulfide isomerase (PDI), thereby ensuring the correct folding and assembly of proteins that contain disulfide bonds in their native state.
Glutaredoxins are small redox enzymes of approximately one hundred amino-acid residues that use glutathione as a cofactor. In humans this oxidation repair enzyme is also known to participate in many cellular functions, including redox signaling and regulation of glucose metabolism. Glutaredoxins are oxidized by substrates, and reduced non-enzymatically by glutathione. In contrast to thioredoxins, which are reduced by thioredoxin reductase, no oxidoreductase exists that specifically reduces glutaredoxins. Instead, glutaredoxins are reduced by the oxidation of glutathione. Reduced glutathione is then regenerated by glutathione reductase. Together these components compose the glutathione system.
Protein disulfide-isomerase A3 (PDIA3), also known as glucose-regulated protein, 58-kD (GRP58), is an isomerase enzyme. This protein localizes to the endoplasmic reticulum (ER) and interacts with lectin chaperones calreticulin and calnexin (CNX) to modulate folding of newly synthesized glycoproteins. It is thought that complexes of lectins and this protein mediate protein folding by promoting formation of disulfide bonds in their glycoprotein substrates.
Peptidyl-prolyl cis-trans isomerase B is an enzyme that is encoded by the PPIB gene. As a member of the peptidyl-prolyl cis-trans isomerase (PPIase) family, this protein catalyzes the cis-trans isomerization of proline imidic peptide bonds, which allows it to regulate protein folding of type I collagen. Generally, PPIases are found in all eubacteria and eukaryotes, as well as in a few archaebacteria, and thus are highly conserved.
Protein disulfide-isomerase, also known as the beta-subunit of prolyl 4-hydroxylase (P4HB), is an enzyme that in humans encoded by the P4HB gene. The human P4HB gene is localized in chromosome 17q25. Unlike other prolyl 4-hydroxylase family proteins, this protein is multifunctional and acts as an oxidoreductase for disulfide formation, breakage, and isomerization. The activity of P4HB is tightly regulated. Both dimer dissociation and substrate binding are likely to enhance its enzymatic activity during the catalysis process.
Microsomal triglyceride transfer protein large subunit is a protein that in humans is encoded by the MTTP gene.
Endoplasmic reticulum protein 29 (ERp29) is a chaperone protein that in humans is encoded by the ERP29 gene.
ERO1-like protein alpha is a protein that in humans is encoded by the ERO1L gene.
Endoplasmic reticulum resident protein 44 (ERp44) also known as thioredoxin domain-containing protein 4 (TXNDC4) is a protein that in humans is encoded by the ERP44 gene.
Thioredoxin domain-containing protein 12 is a protein that in humans is encoded by the TXNDC12 gene.
Thioredoxin domain-containing protein 5 is a protein that in humans is encoded by the TXNDC5 gene.
Protein disulfide-isomerase TMX3 is an enzyme that in humans is encoded by the TMX3 gene.
DsbA is a bacterial thiol disulfide oxidoreductase (TDOR). DsbA is a key component of the Dsb family of enzymes. DsbA catalyzes intrachain disulfide bond formation as peptides emerge into the cell's periplasm.
ERp27 is a homologue of PDI, localised to the Endoplasmic Reticulum. The structure of ERp27 has been solved by both X-ray crystallography and NMR spectroscopy, showing it to be composed of two thioredoxin-like domains with homology to the non-catalytic b and b' domains of PDI. The function of ERp27 is unknown, but on the basis of its homology with PDI it is thought to possess chaperone activity.
Protein disulfide isomerase family A member 2 is a protein that in humans is encoded by the PDIA2 gene.
References
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- ↑ Holmgren A (1989). "Thioredoxin and glutaredoxin systems". J. Biol. Chem. 264 (24): 13963–13966. PMID 2668278.
- ↑ Holmgren A (1995). "Thioredoxin structure and mechanism: conformational changes on oxidation of the active-site sulfhydryls to a disulfide". Structure. 3 (3): 239–243. doi: 10.1016/s0969-2126(01)00153-8 . PMID 7788289.
- 1 2 Martin JL (1995). "Thioredoxin--a fold for all reasons". Structure. 3 (3): 245–250. doi: 10.1016/S0969-2126(01)00154-X . PMID 7788290.
- ↑ Puig A, Lyles MM, Noiva R, Gilbert HF (1994). "The role of the thiol/disulfide centers and peptide binding site in the chaperone and anti-chaperone activities of protein disulfide isomerase". J. Biol. Chem. 269 (29): 19128–19135. PMID 7913469.
- 1 2 3 Lyles MM, Gilbert HF (1994). "Mutations in the thioredoxin sites of protein disulfide isomerase reveal functional nonequivalence of the N- and C-terminal domains". J. Biol. Chem. 269 (49): 30946–30952. PMID 7983029.
- ↑ Wang CC, Song JL (1995). "Chaperone-like activity of protein disulfide-isomerase in the refolding of rhodanese". Eur. J. Biochem. 231 (2): 312–316. doi:10.1111/j.1432-1033.1995.tb20702.x. PMID 7635143.
- ↑ Mazzarella RA, Srinivasan M, Haugejorden SM, Green M (1990). "ERp72, an abundant luminal endoplasmic reticulum protein, contains three copies of the active site sequences of protein disulfide isomerase". J. Biol. Chem. 265 (2): 1094–1101. PMID 2295602.
- 1 2 Gleason FK, Eklund H, Saarinen M (1995). "Crystal structure of thioredoxin-2 from Anabaena". Structure. 3 (10): 1097–1108. doi: 10.1016/s0969-2126(01)00245-3 . PMID 8590004.