Protein Disulfide Isomerase: A Critical Evaluation of Its Function in Disulfide Bond Formation

Hatahet, Feras; Ruddock, Lloyd W.

doi:10.1089/ars.2009.2466

Cited by 588 publications

(678 citation statements)

References 340 publications

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“…To date, approximately 20 PDI family members have been identified, including soluble and transmembrane-containing proteins, most of which are ubiquitously expressed (Ellgaard and Ruddock 2005). PDI is a canonical member of the PDI family and also functions as a molecular chaperone (Hatahet et al 2009). PDI is composed of two active Trx-like domains (called the a and a 0 domains) that are linked by two inactive Trx-like domains (called the b and b 0 domains), and its primary substrate binding site is located in the b 0 domain.…”

Section: Disulfide Bond Formationmentioning

confidence: 99%

Protein Folding and Quality Control in the ER

Araki

Nagata

2011

Cold Spring Harbor Perspectives in Biology

326

285

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The endoplasmic reticulum (ER) uses an elaborate surveillance system called the ER quality control (ERQC) system. The ERQC facilitates folding and modification of secretory and membrane proteins and eliminates terminally misfolded polypeptides through ER-associated degradation (ERAD) or autophagic degradation. This mechanism of ER protein surveillance is closely linked to redox and calcium homeostasis in the ER, whose balance is presumed to be regulated by a specific cellular compartment. The potential to modulate proteostasis and metabolism with chemical compounds or targeted siRNAs may offer an ideal option for the treatment of disease.

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Section: Disulfide Bond Formationmentioning

confidence: 99%

Protein Folding and Quality Control in the ER

Araki

Nagata

2011

Cold Spring Harbor Perspectives in Biology

326

285

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“…This appears the case, as kinetic rates for direct glutathione oxidation/reduction are too slow to be physiologically relevant [9]. Electron affinity (and therefore redox potential) is broadly determined by the proximity of the two cysteines, with the proximity determined by the current structure of the protein [46]. Cysteines that are in the correct orientation will have a low electron affinity and easily form disulfide bonds, while cysteines that are not in the correct orientation will have a high electron affinity and will have unstable disulfide bonds.…”

Section: Discussionmentioning

confidence: 99%

Imbalance of heterologous protein folding and disulfide bond formation rates yields runaway oxidative stress

et al. 2012

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BackgroundThe protein secretory pathway must process a wide assortment of native proteins for eukaryotic cells to function. As well, recombinant protein secretion is used extensively to produce many biologics and industrial enzymes. Therefore, secretory pathway dysfunction can be highly detrimental to the cell and can drastically inhibit product titers in biochemical production. Because the secretory pathway is a highly-integrated, multi-organelle system, dysfunction can happen at many levels and dissecting the root cause can be challenging. In this study, we apply a systems biology approach to analyze secretory pathway dysfunctions resulting from heterologous production of a small protein (insulin precursor) or a larger protein (α-amylase).ResultsHAC1-dependent and independent dysfunctions and cellular responses were apparent across multiple datasets. In particular, processes involving (a) degradation of protein/recycling amino acids, (b) overall transcription/translation repression, and (c) oxidative stress were broadly associated with secretory stress.ConclusionsApparent runaway oxidative stress due to radical production observed here and elsewhere can be explained by a futile cycle of disulfide formation and breaking that consumes reduced glutathione and produces reactive oxygen species. The futile cycle is dominating when protein folding rates are low relative to disulfide bond formation rates. While not strictly conclusive with the present data, this insight does provide a molecular interpretation to an, until now, largely empirical understanding of optimizing heterologous protein secretion. This molecular insight has direct implications on engineering a broad range of recombinant proteins for secretion and provides potential hypotheses for the root causes of several secretory-associated diseases.

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“…However, there are many potential redox partners, as the mammalian ER contains 20 proteins with a Trx-like fold, 12 of which also have at least one CXXC motif (for review, see ref. 14). The most abundant and best-studied member of this family is PDI, which is a major catalyst of disulfide bridge formation in newly synthesized secretory and membrane proteins.…”

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confidence: 99%

Vitamin K epoxide reductase prefers ER membrane-anchored thioredoxin-like redox partners

Schulman

Wang

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

134

159

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Vitamin K epoxide reductase (VKOR) sustains blood coagulation by reducing vitamin K epoxide to the hydroquinone, an essential cofactor for the γ-glutamyl carboxylation of many clotting factors. The physiological redox partner of VKOR remains uncertain, but is likely a thioredoxin-like protein. Here, we demonstrate that human VKOR has the same membrane topology as the enzyme from Synechococcus sp., whose crystal structure was recently determined. Our results suggest that, during the redox reaction, Cys43 in a luminal loop of human VKOR forms a transient disulfide bond with a thioredoxin (Trx)-like protein located in the lumen of the endoplasmic reticulum (ER). We screened for redox partners of VKOR among the large number of mammalian Trx-like ER proteins by testing a panel of these candidates for their ability to form this specific disulfide bond with human VKOR. Our results show that VKOR interacts strongly with TMX, an ER membrane-anchored Trx-like protein with a unique CPAC active site. Weaker interactions were observed with TMX4, a close relative of TMX, and ERp18, the smallest Trx-like protein of the ER. We performed a similar screen with Ero1-α, an ER-luminal protein that oxidizes the Trx-like protein disulfide isomerase. We found that Ero1-α interacts with most of the tested Trx-like proteins, although only poorly with the membrane-anchored members of the family. Taken together, our results demonstrate that human VKOR employs the same electron transfer pathway as its bacterial homologs and that VKORs generally prefer membrane-bound Trx-like redox partners.disulfide bond formation | warfarin | quinone | blood coagulation | electron transfer

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Protein Disulfide Isomerase: A Critical Evaluation of Its Function in Disulfide Bond Formation

Cited by 588 publications

References 340 publications

Protein Folding and Quality Control in the ER

Protein Folding and Quality Control in the ER

Imbalance of heterologous protein folding and disulfide bond formation rates yields runaway oxidative stress

Vitamin K epoxide reductase prefers ER membrane-anchored thioredoxin-like redox partners

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