Molecular Characterization of a Pancreas-Specific Protein Disulfide Isomerase, PDIp

Desilva, Mark G.; Notkins, Abner Louis; Lan, Michael S.

doi:10.1089/dna.1997.16.269

Cited by 47 publications

(39 citation statements)

References 28 publications

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“…The PDI homologue PDIp is expressed specifically in this organ, and although PDIp can use hydroxyaryl groups as ligands (32), it could in theory replace PDI function in islets. However, like others (29) we find that PDIp and PDI expression patterns are similar, and that PDIp is expressed exclusively in acinar cells. This suggests that further analysis of the islet-specific physiology of Ero1␤ electron donors may be worthwhile, because tissue-specific differences in the control of disulfide bond formation may provide an opening for therapeutic intervention in pancreatic protein secretion and type 2 diabetes.…”

Section: Discussionsupporting

confidence: 88%

“…Pancreas sections stained for the pancreas-specific PDI, PDIp, showed expression of this enzyme in the acinar cells and weak staining of islets, as expected (Fig. 3, C and D) (29). Pancreatic islets were specif-…”

Section: Ero1␤ and Pdi Are Both Expressed In The Pancreas But Show DIsupporting

confidence: 82%

“…The polyclonal rabbit anti-sera against PDI, Ero1␣ (D5), and ERp57 have been described previously (18). The polyclonal PDIp antiserum was a gift from M. Lan (29). Polyclonal antisera against BiP and insulin (H-86) (both Santa Cruz Biotechnology), the mouse monoclonal antibody HA-7 (Sigma), and the anti-myc antibody 9B11 and the anti-myc polyclonal antibody (both Cell Signaling) were commercially available.…”

Section: Methodsmentioning

confidence: 99%

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Tissue-specific Expression and Dimerization of the Endoplasmic Reticulum Oxidoreductase Ero1β

Dias-Gunasekara

Gubbens

Lith

et al. 2005

Journal of Biological Chemistry

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Endoplasmic reticulum oxidoreductases (Eros) are essential for the formation of disulfide bonds. Understanding disulfide bond catalysis in mammals is important because of the involvement of protein misfolding in conditions such as diabetes, arthritis, cancer, and aging. Mammals express two related Ero proteins, Ero1␣ and Ero1␤. Ero1␤ is incompletely characterized but is of physiological interest because it is induced by the unfolded protein response. Here, we show that Ero1␤ can form homodimers and mixed heterodimers with Ero1␣, in addition to Ero-PDI dimers. Ero-Ero dimers require the Ero active site, occur in vivo, and can be modeled onto the Ero1p crystal structure. Our data indicate that the Ero1␤ protein is constitutively strongly expressed in the stomach and the pancreas, but in a cell-specific fashion. In the stomach, selective expression of Ero1␤ occurs in the enzyme-producing chief cells. In pancreatic islets, Ero1␤ expression is high, but is inversely correlated with PDI and PDIp levels, demonstrating that cell-specific differences exist in the regulation of oxidative protein folding in vivo.Protein folding in the ER 5 attracts considerable interest because the failure of a protein to fold can lead to a host of genetic and acquired diseases (1), ranging from cystic fibrosis to ␣1 anti-trypsin deficiency (2). Professional secretory cells in particular must regulate the synthesis of their ER membranes and chaperones to cope with the demands of increased protein production. This is achieved through ER to nucleus signaling pathways, mediated by the trans-membrane associated proteins Ire1␣, PERK, and ATF6 (3). ATF6 and Ire1␣ induce the transcription of XBP1 and the splicing of its mRNA, culminating in the expression of UPR target genes (4). XBP1 is required for B cell maturation into antibody-producing plasma cells (5), and recently, XBP1 and chronic unfolded protein responses have been implicated in obesity and the onset of type 2 diabetes (6), suggesting that targeting physiological unfolded protein responses may have therapeutic value in this disease.Disulfide bond formation is an essential component of the protein folding process, and disulfide bonds are required for structural stability, enzymatic function, and regulation of protein activity (7). The catalytic events involving the oxidation, reduction, and isomerization of disulfide bonds take place in the ER. During protein oxidation, PDI introduces native disulfide bonds into substrate proteins, and is reoxidized by the Ero proteins (Ero1p in yeast, Ero1␣ and Ero1␤ in humans) (8 -11). In yeast, Pdi1p is capable of both oxidizing and isomerizing disulfide bonds, although the relative importance of each function has been debated (12). In humans, PDI also contributes to collagen biosynthesis as a component of the prolyl-4-hydroxlase complex (13) and can act as a component of the ER degradation machinery, particularly with respect to the unfolding and retro-translocation of toxins (14). Numerous PDI homologues exist in yeast (Mpd1p, Mpd2p, Eps1p, and Eug...

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Section: Discussionsupporting

confidence: 88%

Section: Ero1␤ and Pdi Are Both Expressed In The Pancreas But Show DIsupporting

confidence: 82%

Section: Methodsmentioning

confidence: 99%

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Tissue-specific Expression and Dimerization of the Endoplasmic Reticulum Oxidoreductase Ero1β

Dias-Gunasekara

Gubbens

Lith

et al. 2005

Journal of Biological Chemistry

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“…PDI in vitro and in vivo is a general catalyst of native disulfide bond formation, whereas PDIp appears to play a similar role but with different substrate specificity and a specific localization in the acinar cells in the pancreas (41,42). ERp57 appears to be a general catalyst of native disulfide bond formation for glycosylated proteins, which it does not bind directly, but rather binds via an interaction with the ER-resident lectins CRT and CNX (43,44).…”

Section: Discussionmentioning

confidence: 99%

ERp27, a New Non-catalytic Endoplasmic Reticulum-located Human Protein Disulfide Isomerase Family Member, Interacts with ERp57

Alanen

Williamson

Howard

et al. 2006

Journal of Biological Chemistry

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Protein folding and quality control in the endoplasmic reticulum are critical processes for which our current understanding is far from complete. Here we describe the functional characterization of a new human 27.7-kDa protein (ERp27). We show that ERp27 is a two-domain protein located in the endoplasmic reticulum that is homologous to the non-catalytic b and b domains of protein disulfide isomerase. ERp27 was shown to bind ⌬-somatostatin, the standard test peptide for protein disulfide isomerase-substrate binding, and this ability was localized to the second domain of ERp27. An alignment of human ERp27 and human protein disulfide isomerase allowed for the putative identification of the peptide binding site of ERp27 indicating conservation of the location of the primary substrate binding site within the protein disulfide isomerase family. NMR studies revealed a significant conformational change in the b-like domain of ERp27 upon substrate binding, which was not just localized to the substrate binding site. In addition, we report that ERp27 is bound by ERp57 both in vitro and in vivo by a similar mechanism by which ERp57 binds calreticulin.The formation of native disulfide bonds in the endoplasmic reticulum (ER) 2 is a complex, but essential, process in the biogenesis of many proteins, which pass beyond the carefully regulated environment of the cell. The folding process can occur via multiple parallel pathways within a protein (see for example Ref. 1), and this process can be catalyzed in vivo by different biological molecules. For example, there appears to be at least three parallel pathways for oxidation (disulfide bond formation) in substrate proteins, direct oxidation by Ero1 (2-4) or flavin-dependent sulfhydryl oxidases (5, 6), oxidation catalyzed by proteins belonging to the thioredoxin superfamily (for reviews see Refs. 7-9), and oxidation by low molecular weight compounds such as oxidized glutathione (10, 11).The first class of enzymes reported to be involved in disulfide bond formation was the protein disulfide isomerase (PDI) family (7,9,12). Although the founding member of this family, PDI, is sufficient in vitro, when combined with a physiological glutathione redox buffer, to refold reduced protein substrates or to isomerize substrates with incorrect disulfide bonds (13-15), it is clear that in vivo there exists a large family of enzymes. There is evidence that the exact make-up of this family is species-dependent, with, as an extreme example, the yeast Saccharomyces cerevisiae having five reported family members (16), whereas humans have at least seventeen (9), not all of which have been characterized yet. Although the family name suggests that all of the members of the family are able to catalyze isomerization reactions in folding protein substrates, this is not the case. For example, one sub-group of the family, which includes ERp28/29 (17) and Drosophila wind protein (18), lacks both cysteines from the CXXC active site motif that are essential for the catalysis of dithiol-disulfide exchange rea...

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“…An interesting example is the pancreas-specific PDI protein, PDIp, which is co-expressed along with PDI in acinar cells. Like the yeast PDI, PDIp is also glycosylated, but it lacks the acidic c domain (Desilva et al, 1997). Cross-linking experiments indicate that PDIp may interact with misfolded proteins but not native proteins, possibly through interaction with tyrosine and tryptophan residues (Klappa et al, 1998b) .…”

Section: The Protein Disulfide Isomerase Familymentioning

confidence: 99%

Glycoprotein Folding in the Endoplasmic Reticulum

Benham

Braakman

2000

Critical Reviews in Biochemistry and Molecular Biology

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Our understanding of eukaryotic protein folding in the endoplasmic reticulum has increased enormously over the last 5 years. In this review, we summarize some of the major research themes that have captivated researchers in this field during the last years of the 20th century. We follow the path of a typical protein as it emerges from the ribosome and enters the reticular environment. While many of these events are shared between different polypeptide chains, we highlight some of the numerous differences between proteins, between cell types, and between the chaperones utilized by different ER glycoproteins. Finally, we consider the likely advances in this field as the new century unfolds and we address the prospect of a unified understanding of how protein folding, degradation, and translation are coordinated within a cell.

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Molecular Characterization of a Pancreas-Specific Protein Disulfide Isomerase, PDIp

Cited by 47 publications

References 28 publications

Tissue-specific Expression and Dimerization of the Endoplasmic Reticulum Oxidoreductase Ero1β

Tissue-specific Expression and Dimerization of the Endoplasmic Reticulum Oxidoreductase Ero1β

ERp27, a New Non-catalytic Endoplasmic Reticulum-located Human Protein Disulfide Isomerase Family Member, Interacts with ERp57

Glycoprotein Folding in the Endoplasmic Reticulum

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