Association and dissociation of protein disulfide isomerase

Yu, Xuan-Chuan; Wang, Chih‐Chen; Tsou, Chen‐Lu

doi:10.1016/0167-4838(94)90058-2

Cited by 23 publications

(21 citation statements)

References 15 publications

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“…Although a rather different behavior could be observed for different mutants, PDI tetramer was found in all samples. Similar to the previous report (33), the PDI tetramer that occurred in the CK refolding process was not formed by cross-linking of disulfides between PDI dimers but rather by specific oligomerization interfaces. The effect of N CC : B CC :C SS on CK refolding was almost the same as that of WT PDI, which suggested that the mutations of Cys in the aЈ domain did not affect the function of PDI in its assisting CK refolding.…”

Section: Pdi Exhibits Both Anti-chaperone and Chaperone Activity Insupporting

confidence: 70%

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Catalysis of Creatine Kinase Refolding by Protein Disulfide Isomerase Involves Disulfide Cross-link and Dimer to Tetramer Switch

Zhao

Xie

et al. 2005

Journal of Biological Chemistry

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Protein disulfide isomerase (PDI) functions as an isomerase to catalyze thiol:disulfide exchange, as a chaperone to assist protein folding, and as a subunit of prolyl-4-hydroxylase and microsomal triglyceride transfer protein. At a lower concentration of 0.2 M, PDI facilitated the aggregation of unfolded rabbit muscle creatine kinase (CK) and exhibited anti-chaperone activity, which was shown to be mainly due to the hydrophobic interactions between PDI and CK and was independent of the cross-linking of disulfide bonds. At concentrations above 1 M, PDI acted as a protector against aggregation but an inhibitor of reactivation during CK refolding. The inhibition effect of PDI on CK reactivation was further characterized as due to the formation of PDI-CK complexes through intermolecular disulfide bonds, a process involving Cys-36 and Cys-295 of PDI. Two disulfide-linked complexes containing both PDI and CK were obtained, and the large, soluble aggregates around 400 kDa were composed of 1 molecule of tetrameric PDI and 2 molecules of inactive intermediate dimeric CK, whereas the smaller one, around 200 kDa, was formed by 1 dimeric PDI and 1 dimeric CK. To our knowledge this is the first study revealing that PDI could switch its conformation from dimer to tetramer in its functions as a foldase. According to the observations in this research and our previous study of the folding pathways of CK, a working model was proposed for the molecular mechanism of CK refolding catalyzed by PDI.In eukaryotes, all the nascent outer membrane and secreted proteins are synthesized and fold to their native structures in the lumen of endoplasmic reticulum. The specialized compartment provides a favorable environment for native disulfide bond formation, which is often the rate-limiting step in the folding of many proteins. Endoplasmic reticulum is abundant in molecular chaperones and folding catalysts, among which the most abundant and efficient catalyst of disulfide bond formation is protein disulfide isomerase (PDI, 1 EC 5.3.4.1) (1-3). PDI is a multidomain and multifunction homodimer. It comprises four thioredoxin-like domains, a, b, bЈ, and aЈ, plus a linker region between bЈ and aЈ and a C-terminal acid extension (2, 4, 5). Each of the two catalytic domains, a and aЈ, contains a WCGHCK motif, responsible for the isomerase activity (6). In vitro studies showed that the bЈ domain provides the principle peptide binding site, whereas the other domains should also be involved when the protein substrates have a substantial secondary structure (7, 8). The latest study (9) demonstrated the existence of a ligand binding site in the bЈ domain, which was a small hydrophobic pocket defined as Much effort has been devoted to investigating the catalytic mechanism of PDI since the first report published more than 40 years ago (10). As an enzyme, the specific binding to its substrate is a basic property of PDI, and the nature of the interaction between PDI and its substrates plays a crucial role in its activity of accelerating steps in protein fol...

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Section: Pdi Exhibits Both Anti-chaperone and Chaperone Activity Insupporting

confidence: 70%

“…It has been widely accepted that PDI is a dimer, although it had been shown to be a mixture of dimer and tetramer at 4°C and pH 7.5 in a previous study (33). The changes from dimer to oligomer, however, have never been reported to be required for PDI to function as a chaperone or foldase.…”

Section: Pdi Exhibits Both Anti-chaperone and Chaperone Activity Inmentioning

confidence: 95%

Catalysis of Creatine Kinase Refolding by Protein Disulfide Isomerase Involves Disulfide Cross-link and Dimer to Tetramer Switch

Zhao

Xie

et al. 2005

Journal of Biological Chemistry

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“…PDI and ERp29 have been shown to oligomerize under certain conditions (Pace and Dixon, 1979;Yu et al, 1994;Mkrtchian et al, 1998b). In contrast, other studies indicated that PDI (Solovyov and Gilbert, 2004;Li et al, 2006) and ERp57 (Frickel et al, 2004) exist as monomers.…”

Section: Discussionmentioning

confidence: 77%

“…The oxido-reductase activity of members of this family including PDI, ERp72, and ERp57 depends on the active site double-cysteine motif, which is absent in other redox-inactive PDI-like proteins (e.g., ERp27, ERp29, PDILT, TMX2; Ellgaard and Ruddock, 2005). Under certain conditions, PDI and ERp29 were shown to form dimers or higher oligomers (Pace and Dixon, 1979;Yu et al, 1994;Mkrtchian et al, 1998b). Other studies indicated that PDI (Solovyov and Gilbert, 2004;Li et al, 2006) and ERp57 (Frickel et al, 2004) exist as monomers.…”

Section: Introductionmentioning

confidence: 99%

Dimerization of ERp29, a PDI-like Protein, Is Essential for Its Diverse Functions

Rainey-Barger

Mkrtchian

Tsai

2007

MBoC

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Protein disulfide isomerase (PDI)-like proteins act as oxido-reductases and chaperones in the endoplasmic reticulum (ER).How oligomerization of the PDI-like proteins control these activities is unknown. Here we show that dimerization of ERp29, a PDI-like protein, regulates its protein unfolding and escort activities. We have demonstrated previously that ERp29 induces the local unfolding of polyomavirus in the ER, a step required for viral infection. We now find that, in contrast to wild-type ERp29, a mutant ERp29 (D42A) that dimerizes inefficiently is unable to unfold polyomavirus or stimulate infection. A compensatory mutation that partially restores dimerization to the mutant ERp29 (G37D/D42A) rescues ERp29 activity. These results indicate that dimerization of ERp29 is crucial for its protein unfolding function. ERp29 was also suggested to act as an escort factor by binding to the secretory protein thyroglobulin (Tg) in the ER, thereby facilitating its secretion. We show that this escort function likewise depends on ERp29 dimerization. Thus our data demonstrate that dimerization of a PDI-like protein acts to regulate its diverse ER activities.

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“…The concentrations of other proteins were determined by measuring the absorbance (A:::) at 280 nm with the following absorption coefficients: 0.9 for PDI [24]; 1.75 for rhodanese [22]; 0.66 for BSA; 2.55 for lysozyme [25]. PDI usually exists as a mixture of dimer and tetramer [26], but since the composition of the active form is not certain, the presence of the promoter form was assumed in molar ratio calculations using a subunit molecular mass of 57 kDa.…”

Section: Methodsmentioning

confidence: 99%

Chaperone‐Like Activity of Protein Disulfide‐Isomerase in the Refolding Of Rhodanese

Song

Wang

1995

European Journal of Biochemistry

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Protein disulfide-isomerase (PDI) in near stoichiometric concentrations promotes reactivation and prevents aggregation of guanidine-hydrochloride-denatured rhodanese during refolding upon dilution. PDI also suppresses aggregation of rhodanese during thermal inactivation. The above-mentioned properties displayed by PDI completely satisfy the definition of chaperone and provide additional evidence to confirm the hypothesis proposed previously [Wang, C. C. & Tsou, C. L. (1993) FASEB J. 7, 1515-15171 that PDI is both an enzyme and a chaperone. Since rhodanese contains no disulfide bonds, the chaperonelike activity of PDI acting on rhodanese is independent of its disulfide-isomerase activity.Keywords. Protein disulfide-isomerase ; chaperone ; rhodanese ; refolding ; aggregation.Protein disulfide isomerase (PDI) is one of the two characterized foldases [I] and is believed to assist nascent peptide folding by catalyzing the formation of disulfide bonds during protein biogenesis [2]. In view of its catalysis of the joining of thiols distantly situated in the peptide sequences and its peptide-binding property with low specificity [3], we have hypothesized that PDI may act both as an enzyme and a chaperone in protein folding [4]. Recently, we have shown that PDI assists the refolding of Gdn . HC1 (guanidine hydrochloride)-denatured GraP-DH (~-glyceraldehyde-3-phosphate dehydrogenase), a protein containing no disulfide bonds, to its native state and increases its reactivation yield by suppressing aggregation in a way closely similar to the action of a chaperone [5]. It has also been suggested by a few authors that PDI may have chaperone function reported the chaperone and antichaperone activity of PDI in the oxidative refolding of lysozyme. However, Lilie et al. [lo] found no chaperone-like effect of PDI on the refolding of the antibody Fab (antigen-binding antibody fragment consisting of the entire light chain and the two N-terminal domains of the heavy chain) with intact disulfide bonds at pH 7.0 under oxidizing conditions. LaMantia and Lennarz [I I] indicated that the isomerase activity is not essential for cell viability, which may require instead some other functions of PDI.In order to provide more evidence on the chaperone activity of PDI with a target protein that has been well studied in its chaperone-assisted folding 112, 131, we have studied the PDIassisted refolding of Gdn . HC1-denatured rhodanese, which consists of a single chain folded into two domains of equal size containing four cysteine residues [14]. The sequence retains all the information required for targeting, transport, folding, and activity [15], which makes rhodanese a valuable model to study the folding processes of single chain and multidomain proteins. As rhodanese has no disulfide bonds, it is possible to analyze the chaperone activity of PDI independent of its isomerase activity. With target proteins containing disulfide bonds like lysozyme or immunoglobulin, it is difficult to exclude the possibility of disulfide isomerization as the prim...

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Association and dissociation of protein disulfide isomerase

Cited by 23 publications

References 15 publications

Catalysis of Creatine Kinase Refolding by Protein Disulfide Isomerase Involves Disulfide Cross-link and Dimer to Tetramer Switch

Catalysis of Creatine Kinase Refolding by Protein Disulfide Isomerase Involves Disulfide Cross-link and Dimer to Tetramer Switch

Dimerization of ERp29, a PDI-like Protein, Is Essential for Its Diverse Functions

Chaperone‐Like Activity of Protein Disulfide‐Isomerase in the Refolding Of Rhodanese

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