Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Protein Disulfide Isomerase

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101768

Synonyms

Historical Background

The dithiol-disulfide oxidoreductase protein disulfide isomerase (PDI) was discovered in 1963 as the first protein folding chaperone. Research groups led by Brunó Straub (Venetianer and Straub 1963) and Christian B. Anfinsen (Goldberger et al. 1963) independently made pivotal discoveries about an enzyme that reactivated reduced ribonuclease. Straub and coworkers purified the reactivating system from chicken pancreas. Anfinsen studied the system in conjunction with his Nobel-prize-winning work on ribonuclease and purified a system with similar activity from rat liver microsomes. In 1972, the enzyme was given the name protein disulfide isomerase and its official classification number, EC 5.3.4.1. The newly purified protein was identified as the “ribonuclease-reactivating enzyme” and was nearly identical to glutathione-insulin transhydrogenase, causing confusion in the field (Bjelland et al. 1983). Both enzymes catalyze disulfide exchanges, require a thiol for activity, and inactivate insulin. Confusion was cleared with key experiments using covalent chromatography to demonstrate that PDI is more sensitive to reducing conditions than glutathione-insulin transhydrogenase (Hillson and Freedman 1980). The official name was first used in a publication on conformational barriers to disulfide bond formation in 1975 (Hawkins and Freedman 1975). Challenges in monitoring disulfide bond formation and isomerization slowed research on the enzyme until a pivotal review on PDI was published in 1984 (Freedman 1984). Then, in 1985, Edman and colleagues identified the sequence of rat PDI, which led to the discovery that PDI contains sequences highly homologous to the cytoplasmic redox signaling enzyme thioredoxin (Edman et al. 1985). This discovery provided valuable insight into the mechanism of redox reactions catalyzed by PDI and indicated the active sites of PDI contained the critical WCGHC sequence.

PDI has gained much attention in the following years due to its role in cancer, cardiovascular diseases, diabetes, and neurodegenerative diseases such as Huntington’s disease. In addition to its role as an oxidoreductase and molecular chaperone, PDI is important for several other physiological processes, including collagen biosynthesis, antigen presentation, and lipoprotein synthesis. PDI is the beta subunit of prolyl 4-hydroxylase, an essential collagen biosynthesis enzyme, and mutations in PDI lead to bone fragility disorders (Rauch et al. 2015). In recent years, it was discovered that PDI is overexpressed in several cancers. Following this discovery, researchers have found that PDI contributes to tumor growth, progression, and chemotherapeutic resistance. In addition to its role in cancer, PDI has a proapoptotic function in Huntington’s disease and other brain dysfunction diseases (Hoffstrom et al. 2010). Targeting PDI function may be a promising therapeutic approach for multiple human diseases. The structure and function, as well as the role of PDI in various disease states, will be reviewed in detail in the subsequent paragraphs.

Since there are numerous isoforms of PDI, this chapter will focus on PDIA1, as it has been proven to be most relevant to several disease states. However, the other isoforms of PDI will also be discussed in brief. The acronym PDI is often used to refer to PDIA1, but for clarity in this text, PDI will be used when making general statements about the protein family, and specific isoform nomenclature will be used when necessary. Several comprehensive reviews covering a variety of aspects of PDI have been published in recent years (Hatahet and Ruddock 2009; Xu et al. 2014; Benham 2012; Wang et al. 2015).

Domain Structure and Isoforms

The PDI family consists of at least 22 members (Fig. 1) that share at least one thioredoxin-like fold domain (βαβαβαββα) (Hatahet and Ruddock 2009). PDI family members primarily reside in the endoplasmic reticulum (ER) but have also been found in the nucleus, in the cytoplasm, and on the plasma membrane (Table 1). The full-length founding member of the PDI family, PDIA1, contains 508 amino acids, 17 of which form an ER signal peptide that is cleaved from the N-terminal tail in the mature form. Most PDI family members contain the catalytic a and a’ domains that are structurally similar to thioredoxin, with the conserved CXXC active site surrounded by hydrophobic regions. The b and b’ domains are homologous to the a and a’ domains and also contain the thioredoxin-like fold, despite lacking sequence similarity to the a and a’ domains and the CXXC active site. The structures of several domains of mammalian (Wang et al. 2013), yeast (Tian et al. 2006), and fungal (Yagi-Utsumi et al. 2015) PDI have been solved with X-ray crystallography and NMR; however, the full-length structure has yet to be resolved, likely due to its size and flexibility. The complete oxidized and reduced crystallized PDIA1 structure with the exception of the C-terminal extension (i.e., containing abb’a’x domains) demonstrated that the active site of the a’ domain shifts closer to the a domain active site upon reduction, shielding access to the hydrophobic pocket (Fig. 2) (Wang et al. 2013). The b and b’ domains are noncatalytic; the b’ domain is primarily responsible for substrate recognition with help from the a’ domain, and to date, the function of the b domain is unclear. It has been suggested that the b domain in Pdip, a yeast paralog of PDI, plays a role in substrate recognition (Tian et al. 2006). PDIA1 also contains a flexible x linker 19 amino acids long that spans between the a’ and b’ domains. The x region can move to obstruct the substrate binding site in the b’ domain. Therefore this conformational change may regulate the substrate binding cycle of PDI (Tian et al. 2006). PDI also contains an acidic C-terminal extension in which the ER retention signal resides. While the C-terminal region is important for catalytic activity of the a’ domain in yeast PDI (Tian et al. 2006), truncating the C-terminal region of mammalian PDIA1 has little effect (Wang et al. 2013).
Protein Disulfide Isomerase, Fig. 1

Domain structure of PDI family members. Active-site amino acids are shown

Protein Disulfide Isomerase, Table 1

Function and subcellular localization of 22 PDI isoforms

Isoform

Subcellular localization

Function

PDIA1

Endoplasmic reticulum, extracellular space, plasma membrane

Oxidoreductase, chaperone

PDIA2

Endoplasmic reticulum, extracellular space

Oxidoreductase, chaperone, estrogen-binding

PDIA3

Endoplasmic reticulum, extracellular space, nucleus

Oxidoreductase

PDIA4

Endoplasmic reticulum, extracellular space

Oxidoreductase

PDIA5

Endoplasmic reticulum, extracellular space

Oxidoreductase

PDIA6

Endoplasmic reticulum, extracellular space, plasma membrane

Oxidoreductase, chaperone, platelet aggregation and activation

PDIA7

Endoplasmic reticulum

Chaperone, spermatogenesis

PDIA8

Endoplasmic reticulum

Function unknown

PDIA9 (ERp29)

Endoplasmic reticulum, extracellular space

Processes and transports secretory proteins

PDIA10 (ERp44)

Endoplasmic reticulum, extracellular space

Mediator of ER retention of proteins such as ERO1

PDIA11 (TMX1)

Endoplasmic reticulum, extracellular space, nucleus

Oxidoreductase

PDIA12 (TMX2)

Endoplasmic reticulum

Function unknown

PDIA13 (TMX3)

Endoplasmic reticulum

Oxidoreductase

PDIA14 (TMX4)

Endoplasmic reticulum

Function unknown

(TMX5)

Unknown

Potential chaperone

PDIA15 (ERp46)

Endoplasmic reticulum, extracellular space, lysosome, vacuole

Thioredoxin activity

PDIA16 (ERp19, AGR1)

Endoplasmic reticulum

Protein oxidase

PDIA17 (AGR2, HAG-2)

Endoplasmic reticulum, extracellular space

Mucus production and secretion

PDIA18 (AGR3, HAG-3)

Endoplasmic reticulum

Calcium-mediated regulation of ciliary beat frequency

PDIA19 (ERdj5)

Endoplasmic reticulum

Oxidoreductase

PDIB1 (CASQ1)

Endoplasmic reticulum, mitochondrion, plasma membrane

Calcium storage

PDIB2 (CASQ2)

Endoplasmic reticulum, cytosol

Calcium storage

Protein Disulfide Isomerase, Fig. 2

(a) Crystal structures of reduced (4EKZ, red) and oxidized (4EL1, blue) PDIA1. (b) Close up of the CGHC active site of the a domain of reduced PDIA1 and associated arginine residue (green). (c) Domain structure of PDIA1. Domain boundaries are numbered based on full-length PDI

The PDI active sites are located on the a and a’ domains, which share 33.6% identity in PDIA1 and contain the four conserved amino acids Cys-Gly-His-Cys. The cysteine thiols on each domain sit about 30 Å apart when PDIA1 is oxidized and 15 Å apart when PDIA1 is reduced (Wang et al. 2013). The cysteines are responsible for disulfide exchange on PDI and the kinetics of the reactions catalyzed by this enzyme rely on the conformation and pKa of the cysteines. For example, PDI catalyzes both the reduction and oxidation of various substrates, and the more favorable of the two reactions depends on the conformational state and pKa of the active-site cysteine residues. The pKa of the N-terminal active-site cysteine is in the range of 4.4–6.7, lower than the pKa (8.3) of a typical cysteine thiol, allowing it to be more reactive. The pKa of the C-terminal active-site cysteine is much higher than normal at 12.8, allowing it to attack the N-terminal cysteine after it forms a disulfide with the substrate. The inner histidine and glycine amino acids in the active site also affect the pKa of the thiols and the stability of the disulfide state (Hatahet and Ruddock 2009).

Even though the b and b’ domains contain the thioredoxin fold of the a and a’ domains, they are enzymatically inactive and do not contain the CGHC active site. The function of the b domain is still up for debate; however, the b’ domain is responsible for substrate interactions via a hydrophobic pocket. Exposed hydrophobic regions in unfolded or partially folded proteins associate with the hydrophobic region spanning the b’a’ domain, thus allowing PDI to form disulfide bridges necessary for proper protein folding. Interestingly, small molecules binding in the substrate binding pocket enhance PDI activity (Bekendam et al. 2016).

Function and Regulation

PDI catalyzes the reduction, oxidation, and rearrangement of disulfide bonds in nascent polypeptides. PDI is highly abundant in the ER and accounts for up to 0.8% of total cellular protein (Freedman 1984). It is also synthesized downstream of the unfolded protein response (UPR) (Hetz et al. 2013). PDI isoforms are also found on the cell surface and in the nucleus, suggesting PDI has multiple functions. Cell-surface PDI is involved in multiple biological processes, including glioma cell migration (Goplen et al. 2006), T cell migration (Bi et al. 2011), and injury response (Reinhardt et al. 2008). PDI isoforms that lack the ER retention sequence localize to other compartments such as the nucleus to influence gene transcription. For example, ERp57 mainly resides in the ER but contains a nuclear localization signal that shuttles the enzyme to the nucleus in response to stress signals. In addition to its oxidoreductase activity, PDI is also involved in complex formation, substrate recognition, and molecular chaperone function. It is also a necessary component of the microsomal triglyceride transfer protein complex (Wetterau et al. 1990). A whole-body PDIA1 knockout model has not been reported.

PDI activity is regulated by the redox state of its active-site cysteine thiols. In the oxidizing environment of the ER, the enzyme is primed to reduce free thiols on other proteins. ER oxidoreduction 1 (ERO1), a FAD-cofactor-containing enzyme, recycles PDI for reuse (Fig. 3). PDI expression is also regulated by ER stress and the unfolded protein response (Hetz et al. 2013). The UPR is initiated by an overloading burden of unfolded proteins on the ER, and, upon UPR initiation, three central proteins are activated to maintain cellular homeostasis. One of these central effectors, PERK, is a kinase that phosphorylates eIF2α, a transcription factor that translocates to the nucleus and attenuates translation. eIF2α activates the transcription of several genes, including PDI and GRP78.
Protein Disulfide Isomerase, Fig. 3

Role of PDI in the endoplasmic reticulum. PDI catalyzes the oxidation and isomerization of misfolded proteins in the ER. PDI is reoxidized by ERO1, or PRDX4 in the presence of oxidized glutathione. Impairment of PDI activity leads to the unfolded protein response, which activates IRE1, PERK, and ATF6. IRE1 splices XBP1 mRNA, which causes it to translocate to the nucleus and promote gene expression. PERK phosphorylates eIF2a to inhibit translation and activate ATF4. ATF4 translocates to the nucleus and promotes autophagy and cell survival. ATF6 is also modified in the Golgi apparatus and translocated to the nucleus to impact ER biogenesis and ERAD to promote cell survival. ERSE: Endoplasmic reticulum stress element. XBP1u X-box protein 1 unspliced variant, XBP1s X-box protein 1 spliced variant

PDI catalyzes three different types of reactions (Fig. 4). The first is the oxidation of a protein or peptide substrate to the disulfide state. The second is the reduction of a protein or peptide disulfide bond. The third reaction PDI is able to catalyze is an isomerization of a mixed disulfide bond in a protein or peptide substrate. The oxidoreductase activity of PDI depends on the reduction potential and pKa of its active-site cysteine thiols. The N-terminal Cys active site has a low pKa to maintain a sufficiently high reduction potential to form intermediate disulfide species with a protein substrate. The transient heterodimer is attacked by the low- pKa C-terminal thiol in the “escape pathway,” forming an intramolecular bridge and displacing the thiol. A model substrate peptide consisting of 12 amino acids bound PDI with an apparent KM value less than 3 μM in an experiment analyzing disulfide bond formation (Darby and Creighton 1995). While PDI is generally understood to have several folding protein and peptide substrates, only a handful have been experimentally determined. These include bovine pancreatic trypsin inhibitor, Δ-somatostatin, mastoparan, insulin, and RNase. Interestingly, while PDI does exhibit flexibility in its a’ domain through the x linker, substrate binding studies reveal that the protein and peptide substrates of PDI are more likely to change conformation to fit into the hydrophobic binding pocket (Hatahet and Ruddock 2009). After the reaction takes place, oxidized or reduced PDI can be recycled by a number of agents, including glutathione and ERO1.
Protein Disulfide Isomerase, Fig. 4

Multifunctional roles of the PDI family. PDI catalyzes the oxidation (a), reduction (b), and isomerization (c) of cysteine thiols on substrate peptides and proteins

Before ERO1 was discovered in 1998, the consensus was that glutathione, the primary redox buffer in the ER, was the primary oxidizing agent for PDI. However, it is now understood that in its reduced state, PDI is predominantly reoxidized by ERO1. There are two mammalian isoforms of ERO1: ERO1α and ERO1β. ERO1α is well characterized and its activity is tightly regulated by the redox environment. The activity of ERO1β is less well characterized, but it is less tightly regulated than ERO1α. The ERO1 enzymes rely on molecular oxygen as the electron acceptor and in return for each disulfide bond formed, produce one molecule of H2O2. ERO1 primarily oxidizes PDIA1, and, to a lesser extent, ERp46 (Appenzeller-Herzog et al. 2010; Araki et al. 2013). Other PDI isoforms are selectively recycled by enzymes such as peroxiredoxin 4 (PRDX4) and vitamin K epoxide reductase (VKOR).

In addition to ERO1 reoxidation, H2O2, PRDX4, docosahexaenoic acid (DHA), and vitamin K have the ability to reoxidize PDI (Hatahet and Ruddock 2009). Moreover, several members of the PDI family can undergo disulfide exchanges with each other, without the need for an outside oxidant or reductant (Oka et al. 2015). The cysteine thiols in the active site of PDI are common in other redox-sensing proteins. The low pKa value of the active-site thiols (around 4.4–6.7) means that at physiological pH, the residue is deprotonated as a thiolate anion (R-S). The thiol group of typical cysteines is protonated (R-SH) and renders the group unreactive at physiological pH. The charge on the thiolate anion in PDI is stabilized by a charge–charge interaction with the nearby positively charged Arg120 (Lappi et al. 2004). The substrate binding/release cycle of PDI may be dependent on the redox state of the CXXC active sites. Oxidized PDI takes on an open conformation, promoting accessibility of the hydrophobic binding pocket. After PDI transfers a disulfide bond to its substrate, the conformational shift shuts off accessibility to the binding pocket. In addition to redox regulation, PDI can be regulated by other posttranslational modifications, such as S-nitrosylation.

Cell-surface PDI is regulated by S-nitrosylation on the thiol active sites, which has been shown to contribute to neurological diseases such as Alzheimer’s disease (Kim et al. 2000). S-nitrosylation can change protein conformation, regulate protein activity, and alter protein–protein interactions, among other functions. Aberrant S-nitrosylation leads to protein misfolding that can stimulate synaptic loss and contribute to the pathogenesis of Alzheimer’s disease.

PDIA1 also plays a role as the noncatalytic β subunit of prolyl 4-hydroxylase (P4H) (Koivu et al. 1987). The P4H complex consists of two noncatalytic PDI subunits and two catalytic α subunits. P4H resides in the ER and catalyzes the proline hydroxylation of procollagens, crucial for mature collagen function. Hydroxylation of collagen is critical for the stability of the collagen triple helix. PDI is necessary to prevent the α subunit from aggregation and is likely responsible for maintaining ER localization of the complex (Vuori et al. 1992).

Another well-established function of PDI is as a critical component of the microsomal triglyceride transfer protein (MTP) complex (Wetterau et al. 1990). MTP is composed of an αβ heterodimeric complex in which PDI makes up the smaller β subunit. MTP is a lipid transporter necessary for the biosynthesis of apolipoprotein B (apoB)-containing triglyceride-rich lipoproteins, regulation of cholesterol ester synthesis, and propagation of hepatitis C virus. The reduction, oxidation, and isomerization functions of PDI are not necessary for MTP to function properly; therefore, PDI likely plays a role in structural stability and solubilization of the complex (Hussain et al. 2012).

PDI also aids peptide loading onto major histocompatibility complex class 1 (MHC-1) (Yagi-Utsumi et al. 2015). The MHC-1 complex binds antigenic peptides as they are synthesized through the ER and presents the synthesized peptides to cytotoxic T lymphocyte cells.

Functions in Disease

Proper protein folding is essential for cellular homeostasis and signaling. Aberrant PDI expression leads to several types of diseases caused by misfolded proteins (Fig. 5). Therefore, PDI inhibitors may be important for preventing and curing a wide range of diseases. For example, in cancer, PDI is overexpressed to combat the increasing ER load of protein synthesis, (Xu et al. 2014) and knockdown of PDI in breast cancer cells leads to cell death via apoptosis (Hashida et al. 2011). In models of Huntington’s disease, PDI induces apoptosis via mitochondrial membrane permeabilization (MOMP), and inhibition of PDI suppresses cell toxicity (Hoffstrom et al. 2010). Protein folding malfunctions also play an important role in diabetes due to the link between diabetes, misfolding of proinsulin, and the UPR. Malfunctions in PDI caused by mutations in PDIA1 and ERp57 contribute to abnormal motor control and dendritic morphology (Woehlbier et al. 2016).
Protein Disulfide Isomerase, Fig. 5

PDI plays an important role in various disease states. In cancer, PDI folds nascent proteins to contribute to cell migration, invasion, and metastasis. In neurodegenerative diseases, SNO modification of PDI renders the enzyme incapable of protein folding, leading to the formation of Lewy bodies, inclusion bodies, amyloid β and hyperphosphorylated tau. In diabetes, PDI contributes to the production of insulin from proinsulin, but it also inhibits insulin secretion into the bloodstream, preventing insulin from lowering blood glucose levels. In cardiovascular diseases, in particular atherosclerosis, PDI is required for the PDGF-catalyzed vascular smooth muscle cell migration that causes plaque buildup. SNO (S-nitrosylation); PDGF (platelet-derived growth factor)

Cancer

The connection between cancer and several isoforms of PDI has been the subject of intense study for over a decade. In most cases, higher expression of PDI is protective for the cancer cells and correlates with poor patient survival. Inhibition of PDIA1 is cytotoxic to ovarian cancer cells (Xu et al. 2012). In breast cancer mammospheres, knockdown of PDIA1, ERp44, or ERp57 inhibits cell growth (Wise et al. 2016). Increased PDIA3 and PDIA6 gene expression correlates with aggressiveness of primary ductal breast cancer, (Ramos et al. 2015) and high AGR2 expression is inversely correlated with survival in lung cancer patients (Alavi et al. 2015).

Although PDI inhibitors have yet to reach clinical trials, for the past several years, PDI has been actively pursued as a small-molecule drug target. Several PDI inhibitors that interact with the reactive cysteine thiol active site have been identified for ovarian cancer, (Xu et al. 2012) multiple myeloma, (Vatolin et al. 2016), and other cancers. The T8 class of PDIA1 and PDIA4 inhibitors sensitize leukemic and breast cancer cells to etoposide (Eirich et al. 2014). A propynoic acid carbamoyl methyl amide, PACMA31, was demonstrated to be an orally bioavailable PDI inhibitor with anticancer properties against ovarian cancer (Xu et al. 2012). Small-molecule inhibitors of several isoforms of PDI will be efficacious as cancer treatments, and research is actively being pursued in this area.

Neurodegenerative Diseases

A common pathological characteristic of neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and ALS is the misfolding of proteins. Changes in redox homeostasis in such cases can lead to impairments in PDI function. PDI malfunction is involved in protein misfolding in Alzheimer’s, Parkinson’s, and Huntington’s disease, as well as ALS and prion diseases. Increased levels of reactive oxygen species (ROS) and reactive nitrogen species (RNS) can modify target proteins. For example, the reactive thiol group on the CGHC active site of PDI can be modified with a nitric oxide moiety, in a reaction called S-nitrosylation. S-nitrosylation is a posttranslational modification in which nitric oxide species attach to a thiol to form an S-nitrosothiol. It can occur as a form of redox signaling, but has also been implicated in disease states. In the case of Alzheimer’s disease, disruption of normal PDI function by S-nitrosylation triggers an important signaling event that leads to α-synuclein oligomerization (Xu et al. 2014). Interestingly, normally-functioning PDI inhibits tau fibrillization, a possible contributor to the pathogenesis of Alzheimer’s disease.

Similarly, under normal physiological conditions, PDI forms a complex with α-synuclein, which are protein aggregates common in Lewy bodies. PDI prevents protein aggregation in Parkinson’s disease (Xu et al. 2014). Patients with Parkinson’s disease also exhibit upregulated levels of brain PDIp (Conn et al. 2004). This suggests that PDI is upregulated in response to increased levels of ER stress; however, heightened levels of RNS lead to S-nitrosylation of PDI and prevent the enzyme from halting aggregate formation.

PDI inhibitors are also effective in models of Huntington’s disease (Hoffstrom et al. 2010). Huntington’s disease is caused by a mutation in the huntingtin gene that causes the huntingtin protein to fold incorrectly. As a response to the mutant huntingtin protein, PDI localizes to the mitochondrial membrane and induces MOMP, an event in the intrinsic apoptotic pathway. Inhibitors of PDI are in preclinical development as a treatment for Huntington’s disease and may be applicable to a wide range of neurodegenerative diseases.

Diabetes

Dysfunction of human islet amyloid polypeptide (hIAPP) leads to misfolding events in diabetes similar to those contributing to the pathogenesis of Alzheimer’s disease (Montane et al. 2016). In addition, the hyperglycemic and hyperlipidemic conditions that occur with diabetes lead to a disruption in ER homeostasis and consequently upregulate the UPR. PDI interacts with hIAPP to prevent protein aggregation. Therefore, PDI plays an important role in diabetes, but this role varies depending on several conditions (for a review, see Sun et al. 2015). PDI also interacts with proinsulin in the ER of pancreatic β-cells, and blocks insulin export (Rajpal et al. 2012). PDI acts as a retention factor for proinsulin in β-cells and PDI represents an attractive potential target in Type II diabetes.

Other Diseases

The importance of PDI as an ER chaperone and oxidoreductase is realized under pathological conditions. PDI has also been implicated in several other protein misfolding diseases, including liver disease, atherosclerosis, viral infection (Khan et al. 2011), and prion diseases (Benham 2012). Atherosclerosis is the hardening or thickening of the arteries, caused by plaque formation due to high cholesterol levels and other factors. PDI seems to have a protective effect in atherosclerosis, because it is required for platelet-derived growth factor (PDGF)-induced vascular smooth muscle cell migration (Primm and Gilbert 2001). In platelets, PDI is localized in storage granules and on the extracellular surface of cells within the dense tubular system. UPR activation is involved in liver disease onset and progression (Zhang and Wang 2016). In viral infections, thiol-disulfide exchange is important for HIV-1 entry in primary T-lymphocytes and human monocyte-derived macrophages. Both PDI and thioredoxin play essential roles in this process.

Summary

Over 30% of secreted proteins rely on disulfide bond formation to both stabilize their tertiary structure and function properly. Thus, PDI is a crucial protein for the maintenance of cellular protein homeostasis. As a multifunctional protein with oxidoreductase and chaperone activity, PDI can be found not only in the ER but also at the cell surface and in other locations in the cell. PDI overexpression is involved in various cancers, and PDI inhibitors are crucial tools for exploring disease models of cancer, Huntington’s disease, HIV-1 infection, and cardiovascular diseases. Both inhibitors of PDI function and inducers of PDI expression would be beneficial to combat PDI in different scenarios. For example, PDI inhibitors would be beneficial against cancer and viral infection; however, PDI inducers may prove useful against certain cardiovascular diseases. PDI inhibitors are currently under preclinical development for many of these diseases, and compelling research is under way to fully comprehend the involvement of PDI in various disease states.

Notes

Acknowledgments

We acknowledge financial support from the National Cancer Institute, NIH (CA193690).

References

  1. Alavi M, Mah V, Maresh EL, Bagryanova L, Horvath S, Chia D, Goodglick L, Liu AY. High expression of AGR2 in lung cancer is predictive of poor survival. BMC Cancer. 2015;15:655.PubMedPubMedCentralCrossRefGoogle Scholar
  2. Appenzeller-Herzog C, Riemer J, Zito E, Chin KT, Ron D, Spiess M, Ellgaard L. Disulphide production by Ero1 alpha-PDI relay is rapid and effectively regulated. EMBO J. 2010;29:3318–29.PubMedPubMedCentralCrossRefGoogle Scholar
  3. Araki K, Lemura S, Kamiya Y, Ron D, Kato K, Natsume T, Nagata K. Ero1-alpha and PDIs constitute a hierarchical electron transfer network of endoplasmic reticulum oxidoreductases. J Cell Biol. 2013;202:861–74.PubMedPubMedCentralCrossRefGoogle Scholar
  4. Bekendam RH, Bendapudi PK, Lin L, Nag PP, Pu J, Kennedy DR, Feldenzer A, Chiu J, Cook KM, Furie B, Huang M. A substrate-driven allosteric switch that enhances PDI catalytic activity. Nat Commun. 2016;7:12579.PubMedPubMedCentralCrossRefGoogle Scholar
  5. Benham AM. The protein disulfide isomerase family: key players in health and disease. Antioxid Redox Signal. 2012;16:781–9.PubMedCrossRefGoogle Scholar
  6. Bi S, Hong PW, Lee B, Baum LG. Galectin-9 binding to cell surface protein disulfide isomerase regulates the redox environment to enhance T-cell migration and HIV entry. Proc Natl Acad Sci U S A. 2011;108:10650–5.PubMedPubMedCentralCrossRefGoogle Scholar
  7. Bjelland S, Wallevik K, Kroll J, Dixon JE, Morin JE, Freedman RB, Lambert N, Varandani PT, Nafz MA. Immunological identity between bovine preparations of thiol-protein-disulfide oxidoreductase, glutathione-insulin transhydrogenase and protein-disulfide isomerase. Biochim Biophys Acta. 1983;747:197–9.PubMedCrossRefGoogle Scholar
  8. Conn KJ, Gao W, McKee A, Lan MS, Ullman MD, Eisenhauer PB, Fine RE, Wells JM. Identification of the protein disulfide isomerase family member PDIp in experimental Parkinson's disease and Lewy body pathology. Brain Res. 2004;1022:164–72.PubMedCrossRefGoogle Scholar
  9. Darby NJ, Creighton TE. Functional properties of the individual thioredoxin-like domains of protein disulfide isomerase. Biochem. 1995;34:11725–35.CrossRefGoogle Scholar
  10. Edman JC, Ellis L, Blacher RW, Roth RA, Rutter WJ. Sequence of protein disulfide isomerase and implications of its relationship to thioredoxin. Nature. 1985;317:267–70.PubMedCrossRefGoogle Scholar
  11. Eirich J, Braig S, Schyschka L, Servatius P, Hoffmann J, Hecht S, Fulda S, Zahler S, Antes I, Kazmaier U, Sieber SA, Vollmar AM. A small molecule inhibits protein disulfide isomerase and triggers the chemosensitization of cancer cells. Angew Chem Int Ed Eng. 2014;53:12960–5.CrossRefGoogle Scholar
  12. Freedman RB. Native disulfide bond formation in protein-biosynthesis – Evidence for the role of protein disulfide isomerase. Trends Biochem Sci. 1984;9:438–41.CrossRefGoogle Scholar
  13. Goldberger RF, Epstein CJ, Anfinsen CB. Acceleration of reactivation of reduced bovine pancreatic ribonuclease by a microsomal system from rat liver. J Biol Chem. 1963;238:628–35.PubMedGoogle Scholar
  14. Goplen D, Wang J, Enger PO, Tysnes BB, Terzis AJA, Laerum OD, Bjerkvig R. Protein disulfide isomerase expression is related to the invasive properties of malignant glioma. Cancer Res. 2006;66:9895–902.PubMedCrossRefGoogle Scholar
  15. Hashida T, Kotake Y, Ohta S. Protein disulfide isomerase knockdown-induced cell death is cell-line-dependent and involves apoptosis in MCF-7 cells. J Toxicol Sci. 2011;36:1–7.PubMedCrossRefGoogle Scholar
  16. Hatahet F, Ruddock LW. Protein disulfide isomerase: a critical evaluation of its function in disulfide bond formation. Antioxid Redox Signal. 2009;11:2807–50.PubMedCrossRefGoogle Scholar
  17. Hawkins HC, Freedman RB. Randomly reoxidized soybean trypsin-inhibitor and possibility of conformational barriers to disulfide isomerization in proteins. FEBS Lett. 1975;58:7–11.PubMedCrossRefGoogle Scholar
  18. Hetz C, Chevet E, Harding HP. Targeting the unfolded protein response in disease. Nat Rev Drug Discov. 2013;12:703–19.PubMedCrossRefGoogle Scholar
  19. Hillson DA, Freedman RB. Resolution of protein disulfide-isomerase and glutathione-insulin transhydrogenase activities by covalent chromatography – Properties of the purified protein disulfide-isomerase. Biochem J. 1980;191:373–88.PubMedPubMedCentralCrossRefGoogle Scholar
  20. Hoffstrom BG, Kaplan A, Letso R, Schmid RS, Turmel GJ, Lo DC, Stockwell BR. Inhibitors of protein disulfide isomerase suppress apoptosis induced by misfolded proteins. Nat Chem Biol. 2010;6:900–6.PubMedPubMedCentralCrossRefGoogle Scholar
  21. Hussain MM, Rava P, Walsh M, Rana M, Iqbal J. Multiple functions of microsomal triglyceride transfer protein. Nutr Metab. 2012;9:1.CrossRefGoogle Scholar
  22. Khan MM, Simizu S, Lai NS, Kawatani M, Shimizu T, Osada H. Discovery of a small molecule PDI inhibitor that inhibits reduction of HIV-1 envelope glycoprotein gp120. ACS Chem Biol. 2011;6:245–51.PubMedCrossRefGoogle Scholar
  23. Kim HT, Russell RL, Raina AK, Harris PL, Siedlak SL, Zhu X, Petersen RB, Shimohama S, Smith MA, Perry G. Protein disulfide isomerase in Alzheimer disease. Antioxid Redox Signal. 2000;2:485–9.PubMedCrossRefGoogle Scholar
  24. Koivu J, Myllylä R, Helaakoski T, Pihlajaniemi T, Tasanen K, Kivirikko KI. A single polypeptide acts both as the beta subunit of prolyl 4-hydroxylase and as a protein disulfide-isomerase. J Biol Chem. 1987;262:6447–9.PubMedGoogle Scholar
  25. Lappi AK, Lensink MF, Alanen HI, Salo KEH, Lobell M, Juffer AH, Ruddock LW. A conserved arginine plays a role in the catalytic cycle of the protein disulphide isomerases. J Mol Biol. 2004;335:283–95.PubMedCrossRefGoogle Scholar
  26. Montane J, de Pablo S, Obach M, Cadavez L, Castano C, Alcarraz-Vizan G, Visa M, Rodriguez-Comas J, Parrizas M, Servitja JM, Novials A. Protein disulfide isomerase ameliorates beta-cell dysfunction in pancreatic islets overexpressing human islet amyloid polypeptide. Mol Cell Endocrinol. 2016;420:57–65.PubMedCrossRefGoogle Scholar
  27. Oka OBV, Yeoh HY, Bulleid NJ. Thiol-disulfide exchange between the PDI family of oxidoreductases negates the requirement for an oxidase or reductase for each enzyme. Biochem J. 2015;469:279–88.PubMedPubMedCentralCrossRefGoogle Scholar
  28. Rajpal G, Schuiki I, Liu M, Volchuk A, Arvan P. Action of protein disulfide isomerase on proinsulin exit from endoplasmic reticulum of pancreatic β-cells. J Biol Chem. 2012;287:43–7.PubMedCrossRefGoogle Scholar
  29. Ramos FS, Serino LTR, Carvalho CMS, Lima RS, Urban CA, Cavalli IJ, Ribeiro E. PDIA3 and PDIA6 gene expression as an aggressiveness marker in primary ductal breast cancer. Genet Mol Res. 2015;14:6960–7.PubMedCrossRefGoogle Scholar
  30. Rauch F, Fahiminiya S, Majewski J, Carrot-Zhang J, Boudko S, Glorieux F, Mort JS, Bachinger HP, Moffatt P. Cole-Carpenter syndrome is caused by a heterozygous missense mutation in P4HB. Am J Hum Genet. 2015;96:425–31.PubMedPubMedCentralCrossRefGoogle Scholar
  31. Reinhardt C, von Brühl ML, Manukyan D, Grahl L, Lorenz M, Altmann B, Dlugai S, Hess S, Konrad I, Orschiedt L, Machman N, Ruddock L, Massberg S, Engelmann B. Protein disulfide isomerase acts as an injury response signal that enhances fibrin generation via tissue factor activation. J Clin Invest. 2008;118:1110–22.PubMedPubMedCentralGoogle Scholar
  32. Primm TP, Gilbert HF. Hormone binding by protein disulfide isomerase, a high capacity hormone reservoir of the endoplasmic reticulum. J Biol Chem. 2001;276:281–6.PubMedCrossRefGoogle Scholar
  33. Sun JH, Cui JQ, He Q, Chen Z, Arvan P, Liu M. Proinsulin misfolding and endoplasmic reticulum stress during the development and progression of diabetes. Mol Asp Med. 2015;42:105–18.CrossRefGoogle Scholar
  34. Tian G, Xiang S, Noiva R, Lennarz WJ, Schindelin H. The crystal structure of yeast protein disulfide isomerase suggests cooperativity between its active sites. Cell. 2006;124:61–73.PubMedCrossRefGoogle Scholar
  35. Vatolin S, Phillips JG, Jha BK, Govindgari S, Hu J, Grabowski D, Parker Y, Lindner DJ, Zhong F, Distelhorst CW, Smith MR, Cotta C, Xu Y, Chilakala S, Kuang RR, Tall S, Reu FJ. Novel protein disulfide isomerase inhibitor with anticancer activity in multiple myeloma. Cancer Res. 2016;76:3340–50.PubMedCrossRefGoogle Scholar
  36. Venetianer P, Straub F. Enzymic reactivation of reduced ribonuclease. Biochim Biophys Acta. 1963;67:166–8.PubMedCrossRefGoogle Scholar
  37. Vuori K, Pihlajaniemi T, Marttila M, Kivirikko KI. Characterization of the human prolyl 4-hydroxylase tetramer and its multifunctional protein disulfide-isomerase subunit synthesized in a baculovirus expression system. Proc Natl Acad Sci U S A. 1992;89:7467–70.PubMedPubMedCentralCrossRefGoogle Scholar
  38. Wang C, Li W, Ren J, Fang J, Ke H, Gong W, Feng W, Wang CC. Structural insights into the redox-regulated dynamic conformations of human protein disulfide isomerase. Antioxid Redox Signal. 2013;19:36–45.PubMedCrossRefGoogle Scholar
  39. Wang L, Wang X, Wang CC. Protein disulfide-isomerase, a folding catalyst and a redox-regulated chaperone. Free Radic Biol Med. 2015;83:305–13.PubMedCrossRefGoogle Scholar
  40. Wetterau JR, Combs KA, Spinner SN, Joiner BJ. Protein disulfide isomerase is a component of the microsomal triglyceride transfer protein complex. J Biol Chem. 1990;265:9800–7.PubMedPubMedCentralGoogle Scholar
  41. Wise R, Duhachek-Muggy S, Qi Y, Zolkiewski M, Zolkiewska A. Protein disulfide isomerases in the endoplasmic reticulum promote anchorage-independent growth of breast cancer cells. Breast Cancer Res Treat. 2016;157:241–52.PubMedPubMedCentralCrossRefGoogle Scholar
  42. Woehlbier U, Colombo A, Saaranen MJ, Perez V, Ojeda J, Bustos FJ, Andreu CI, Torrez M, Valenzuela V, Medinas DB, Rozas P, Vidal RL, Lopez-Gonzalez R, Salameh J, Fernandez-Collemann S, Munoz N, Matus S, Armisen R, Sagredo A, Palma K, Irrazabal T, Almeida S, Gonzalez-Perez P, Campero M, Gao FB, Henny P, van Zundert B, Ruddock LW, Concha ML, Henriquez JP, Brown RH, Hetz C. ALS-linked protein disulfide isomerase variants cause motor dysfunction. EMBO J. 2016;35:845–65.PubMedPubMedCentralCrossRefGoogle Scholar
  43. Xu S, Butkevich AN, Yamada R, Zhou Y, Debnath B, Duncan R, Zandi E, Petasis NA, Neamati N. Discovery of an orally active small-molecule irreversible inhibitor of protein disulfide isomerase for ovarian cancer treatment. Proc Natl Acad Sci U S A. 2012;109:16348–53.PubMedPubMedCentralCrossRefGoogle Scholar
  44. Xu S, Sankar S, Neamati N. Protein disulfide isomerase: a promising target for cancer therapy. Drug Discov Today. 2014;19:222–40.PubMedCrossRefGoogle Scholar
  45. Yagi-Utsumi M, Satoh T, Kato K. Structural basis of redox-dependent substrate binding of protein disulfide isomerase. Sci Rep. 2015;5:13909.PubMedPubMedCentralCrossRefGoogle Scholar
  46. Zhang L, Wang HH. The essential functions of endoplasmic reticulum chaperones in hepatic lipid metabolism. Dig Liver Dis. 2016;48:709–16.PubMedCrossRefGoogle Scholar

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© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of Medicinal Chemistry, College of PharmacyTranslational Oncology Program, University of MichiganAnn ArborUSA