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Information on EC 5.3.4.1 - protein disulfide-isomerase and Organism(s) Mus musculus and UniProt Accession P27773
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5.3.4.1 protein disulfide-isomeraseIUBMB Comments
Needs reducing agents or partly reduced enzyme; the reaction depends on sulfhydryl-disulfide interchange.
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Word Map
- 5.3.4.1
- collagen
- laminin
- integrins
- endothelial
- actin
- fibrosis
-
adhesive
-
basement
- mesenchymal
- vessel
- fiber
- metastasis
- proteoglycans
- vitronectin
- fibrinogen
- matrices
- nephropathy
- albumin
- gelatin
-
interstitial
-
mesangial
- platelet
- monolayer
- cytoskeleton
- glomerular
- rgd
- vimentin
- e-cadherin
-
cell-cell
- adhesions
- zeta
- myofibroblasts
- willebrand
-
epithelial-mesenchymal
- factor-beta
- fak
- fibrin
- metalloproteinases
-
preterm
-
dish
-
biomaterials
- procollagens
- heparan
-
alpha-smooth
- dermal
- tgf-beta
- plasminogen
-
fibrillar
- drug development
-
heparin-binding
- synthesis
- thrombospondin
- medicine
- industry
- diagnostics
- pharmacology
- biotechnology
- analysis
The taxonomic range for the selected organisms is: Mus musculus
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria, Archaea
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria, Archaea
Synonyms
fibronectin, pdi, protein disulfide isomerase, erp57, pdia3, protein disulphide isomerase, cabp1, erp44, disulfide isomerase, erp72, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
5'-MD
-
-
-
-
58 kDa glucose regulated protein
-
-
-
-
58 kDa microsomal protein
-
-
-
-
CaBP1
-
-
-
-
CaBP2
-
-
-
-
Cellular thyroid hormone binding protein
-
-
-
-
Disulfide interchange enzyme
-
-
-
-
Disulfide isomerase ER-60
-
-
-
-
DsbA
-
-
-
-
DsbC
-
-
-
-
DsbD
-
-
-
-
endoplasmic reticulum protein EUG1
-
-
-
-
ER58
-
-
-
-
ERp-72 homolog
-
-
-
-
ERp57
ERP59
-
-
-
-
ERP60
-
-
-
-
ERp72
HIP-70
-
-
-
-
Iodothyronine 5'-monodeiodinase
-
-
-
-
P55
-
-
-
-
P58
-
-
-
-
PDI
PDIp
protein disulfide isomerase
-
-
Protein disulfide isomerase P5
-
-
-
-
Protein disulfide isomerase-related protein
-
-
-
-
Protein disulphide isomerase
-
-
-
-
Protein ERp-72
-
-
-
-
R-cognin
-
-
-
-
Rearrangease
-
-
-
-
Reduced ribonuclease reactivating enzyme
-
-
-
-
Retina cognin
-
-
-
-
S-S rearrangase
-
-
-
-
Thyroid hormone-binding protein
-
-
-
-
Thyroxine deiodinase
-
-
-
-
additional information
ERp57
-
-
-
-
ERp72
-
-
-
-
PDI
-
-
-
-
PDIp
-
-
-
-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
isomerization
-
-
-
-
intramolecular oxidoreduction
-
-
-
-
SYSTEMATIC NAME
IUBMB Comments
Protein disulfide-isomerase
Needs reducing agents or partly reduced enzyme; the reaction depends on sulfhydryl-disulfide interchange.
CAS REGISTRY NUMBER
COMMENTARY
37318-49-3
-
SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
neuronal nitric oxide synthase
?
-
the enzyme catalyzes neuronal nitric oxide synthase dimerization
-
-
?
oxidoreductase Ero1
?
-
disulfide bond formation in the oxidoreductase Ero1, endoplasmic reticular protein interacts with PDILT
-
-
?
Proteins
?
-
enzyme may be involved in the formation of intra-chain and inter-chain disulfide bonds in procollagen
-
-
?
Proteins
Proteins
-
native, reduced or with wrong disulfide bonds
with correct disulfide bonds
?
Proteins
Proteins
-
native, reduced or with wrong disulfide bonds
with correct disulfide bonds
?
additional information
?
-
PDIA1, and probably also PDIA3, shows cytotoxic regulatory protein 2, CxRP2, activity in T-cells, acting as perforin inhibitor associated with cytotoxic T cell granules, overview. Perforin is a membrane-permeabilizing protein important to T cell cytotoxic action
-
-
?
additional information
?
-
-
PDILT forms intermolecular disulfide bonds in testis
-
-
?
additional information
?
-
-
PDILT forms intermolecular disulfide bonds, but shows no intramolecular disulfide bonds
-
-
?
additional information
?
-
-
sperm surface protein disulfide isomerase activity plays a role in gamete fusion and sperm-egg interaction, the enzyme mediates conformational changes by thiol-disulfide exchange in fusion-active proteins, participation of ERp57, overview
-
-
?
additional information
?
-
-
the enzyme mediates conformational changes by thiol-disulfide exchange
-
-
?
additional information
?
-
-
PDI is required in vivo for both fibrin generation and platelet thrombus formation
-
-
?
additional information
?
-
-
protein disulfide isomerase directly promotes initiator protein tissue factor-dependent fibrin production during thrombus formation in vivo
-
-
?
additional information
?
-
-
enzyme converts initiator protein tissue factor cysteine residues from glutathionylated to disulfide state
-
-
?
additional information
?
-
-
AGR2 is essential for production of intestinal mucin MUC2, but is not required for establishment of intestinal secretory epithelial cell lineages
-
-
?
additional information
?
-
-
PDI specifically binds 3,3',5-triiodo-L-thyronine
-
-
?
additional information
?
-
-
a cysteine residue in the thioredoxin-like domain of AGR2 forms mixed disulfide bonds with MUC2, mutational analysis of the AGR2-MUC2 interaction, overview
-
-
?
additional information
?
-
-
the enzyme's isomerase activity comprises disulfide reduction, refolding, and oxidation of thiols requiring all four thioredoxin-folded domains in tandem link plus the C-terminal acidic extension
-
-
?
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
neuronal nitric oxide synthase
?
-
the enzyme catalyzes neuronal nitric oxide synthase dimerization
-
-
?
Proteins
?
-
enzyme may be involved in the formation of intra-chain and inter-chain disulfide bonds in procollagen
-
-
?
additional information
?
-
PDIA1, and probably also PDIA3, shows cytotoxic regulatory protein 2, CxRP2, activity in T-cells, acting as perforin inhibitor associated with cytotoxic T cell granules, overview. Perforin is a membrane-permeabilizing protein important to T cell cytotoxic action
-
-
?
additional information
?
-
-
PDILT forms intermolecular disulfide bonds in testis
-
-
?
additional information
?
-
-
sperm surface protein disulfide isomerase activity plays a role in gamete fusion and sperm-egg interaction, the enzyme mediates conformational changes by thiol-disulfide exchange in fusion-active proteins, participation of ERp57, overview
-
-
?
additional information
?
-
-
PDI is required in vivo for both fibrin generation and platelet thrombus formation
-
-
?
additional information
?
-
-
protein disulfide isomerase directly promotes initiator protein tissue factor-dependent fibrin production during thrombus formation in vivo
-
-
?
additional information
?
-
-
AGR2 is essential for production of intestinal mucin MUC2, but is not required for establishment of intestinal secretory epithelial cell lineages
-
-
?
additional information
?
-
-
PDI specifically binds 3,3',5-triiodo-L-thyronine
-
-
?
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
bisphenol A
-
i.e. 2,2-bis(4-hydroxyphenyl)propane, an endocrine disrupting chemical, inhibiting the enzyme's 3,3',5-triiodo-L-thyronine binding activity, its chaperone activity, and its isomerase activity, structural requirements, overview
tetrabromobisphenyl A
-
TBBPA, inhibits PDI 3,3',5-triiodo-L-thyronine binding activity
tetrachlorobisphenyl A
-
TCBPA, inhibits PDI 3,3',5-triiodo-L-thyronine binding activity
bacitracin
-
infusion of blood vessels inhibits platelet thrombus formation and fibrin generation
additional information
no inhibition of CxPR2 activity by treatment with cysteine and serine protease inhibitors E-64 and DCI
-
additional information
-
although PDI can be protective against mutant SOD1 aggregation and toxicity, aberrant S-nitrosylation of critical active site cysteine residues likely inactivates the normal protective function of PDI in amyotrophic lateral sclerosis spinal cords
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
-
the enzyme is present in untreated cells in an inactive S-nitrosylated form, which becomes activated following glutathione depletion via S-denitrosylation
-
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
-
time-dependent decrease in in PDI expression in thrombi following injury. Infusion of monoclonal antibodies against PDI into the circulation of mice lacking the G protein-coupled platelet receptor Par4 prior to vessel wall injury inhibits fibrin generation
-
pancreas-specific protein disulfide isomerase, PDIp, specific expression in pancreatic acinar cells, high expression level of PDIp
-
specific expression of PDIp in gastric chief cells, high expression level of PDIp
additional information
-
enzyme activity increases in response to polyclonal activation by bacterial lipopolysaccharide. Induction of the enzyme is closely coupled to the final stages of differentiation to plasma cells
additional information
-
no or poor expression of PDIp in colon, cecum, and duodenum. PDIp shows a cell-type specific expression in various mouse tissues, in the digestive organs, such as the stomach and pancreas, very high levels of PDIp are selectively expressed in the digestive enzyme-secreting cells
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
-
mice lacking AGR2 are viable but are highly susceptible to colitis, indicating a critical role for AGR2 in protection from disease
physiological function
physiological function
-
PDI is a key enzyme involved in formation of correct pattern of disulfide bonds in proteins. PDI also plays an important role in the hypothalamic-pituitary-thyroid axis, mechanism, overview
physiological function
-
PDI is an abundant enzyme that forms, breaks, and isomerizes disulfide bonds and is therefore an important cellular defense against protein misfolding. PDI can be protective against mutant SOD1 aggregation and toxicity
physiological function
-
PDIp may function as a protein-folding catalyst for secretory digestive enzymes
physiological function
-
the enzyme is involved in myocardial angiogenesis. Protein disulfide isomerase is highly upregulated in hypoxic myocardial capillary endothelial cells, chronic hypoxia increases the survival rate and reduces the infarct size in myocardial ischemia, overview
physiological function
-
the enzyme plays a role in the formation of disulfide bonds in immunoglobulins, it is also involved in disulfide bond formation of the IgG4 subclass of antibody, but catalysis of disulfide bond formation is not rate limiting for IgG4 production
physiological function
-
the protein disulfide isomerase AGR2 is essential for production of intestinal mucin MUC2, a large, cysteine-rich glycoprotein that forms the protective mucus gel lining the intestine
physiological function
-
extracellular protein disulfide isomerase (PDI) regulates ligand-binding activity of alphaMbeta2 integrin and neutrophil recruitment during vascular inflammation. Neutrophil PDI is required for neutrophil adhesion and crawling during tumor necrosis factor-alpha-induced vascular inflammation in vivo
physiological function
-
protein disulfide isomerase directly interacts with beta-actin Cys374 during cell adhesion and spreading and regulates cytoskeleton reorganization
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). PDIA3_MOUSE
505
0
56678
Swiss-Prot
Secretory Pathway (Reliability: 1)
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
65000
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
-
the enzyme molecule has four domains a,a', b, and b', each possessing a thioredoxin fold, the domain a and a' show catalytic sites with the Cys-Gly-His-Cys motif, the b and b' domains possess substrate binding sites, domains b' and a' are linked via linker x, and the enbzyme also posseses a C-terminal acidic alpha-helix containing the endoplasmic reticulum retention signal, domain structure, overview
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
additional information
-
downregulation of protein disulfide isomerase gene expression by siRNA leads to an average 36.8% inhibition of gene expression and correlates with a 3.2fold increase in tumor necrosis factor alpha release into the cell supernatant
additional information
-
mutant Agr2-/- mice lacking AGR2 are viable but are highly susceptible to colitis, the mutant mice show a 3fold reduced Muc2 mRNA level
additional information
-
PDI gene silencing in NS0/2N2 cells by transfection with two different PDI siRNAs, PDI1 and PDI2, respectively. Transiently silencing PDI mRNA in NS0/2N2 cells and increasing the intracellular levels of members of the PDI family, PDI, ERp72, and PDIp, have an effect on the mRNA levels, assembly and secretion of an IgG4 isotype, overview
TEMPERATURE STABILITY
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
70 - 75
CxRP2 is heat sensitive losing substantial activity after 30 min at 70-75°C, overview
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
complete His-Tag purification resin column chromatography and Superdex 200 gel filtration
-
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
DNA sequence determination of testis-specific PDILT, expression in HeLa cells endoplasmic reticulum as Myc-tagged protein
-
PDI, quantitative expression analysis, overexpression in CHO and in NS0/2N2 cells
-
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
PDI is induced by unfolded protein response, UPR, signaling transduction pathways activated by protein misfolding in the endoplasmic reticulum, overview. PDI is upregulated before symptom onset in spinal cords of mutant SOD1G93A mice
-
protein disulfide isomerase is highly upregulated in hypoxic myocardial capillary endothelial cells
-
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
diagnostics
-
the absence of PDIp expression in pancreatic adenocarcinoma may serve as an additional biomarker for pancreatic cancer
medicine
medicine
-
lipopolysaccharide decreases protein disulfide isomerase protein expression by 33% in RAW 264.7 cells. Incubation of the cells with bacitracin significantly decreases tumor necrosis factor alpha gene expression and release. Downregulation of protein disulfide isomerase gene expression by siRNA correlates with a 3.2fold increase in tumor necrosis factor alpha release into the cell supernatant
medicine
-
PDI is required in vivo for both fibrin generation and platelet thrombus formation
medicine
-
protein disulfide isomerase directly promotes initiator protein tissue factor-dependent fibrin production during thrombus formation in vivo. After endothelial denudation of carotid artery, enzyme is released at the injury site from adherent platelets and disrupted vessel walls. Inhibition of the enzyme decreases initiator protein tissue factor-triggered fibrin formation. Enzyme infusion increases fibrin generation at the injury site
medicine
-
the enzyme is a therapeutic target for preventing and treating inappropriate neutrophil sequestration
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Paver, J.L.; Freedman, R.B.; Parkhouse, R.M.E.
Induction of protein disulphide-isomerase during lymphocyte activation and maturation
Biochem. Soc. Trans.
16
56
1988
Mus musculus
-
Myllyl, R.; Koivu, J.; Pihlajaniemi, T.; Kivirikko, K.I.
Protein disulphide-isomerase activity in various cells synthesizing collagen
Eur. J. Biochem.
134
7-11
1983
Gallus gallus, Homo sapiens, Mus musculus
van Lith, M.; Hartigan, N.; Hatch, J.; Benham, A.M.
PDILT, a divergent testis-specific protein disulfide isomerase with a non-classical SXXC motif that engages in disulfide-dependent interactions in the endoplasmic reticulum
J. Biol. Chem.
280
1376-1383
2005
Mus musculus
Ellerman, D.A.; Myles, D.G.; Primakoff, P.
A role for sperm surface protein disulfide isomerase activity in gamete fusion: evidence for the participation of ERp57
Dev. Cell
10
831-837
2006
Mus musculus
Zhou, M.; Jacob, A.; Ho, N.; Miksa, M.; Wu, R.; Maitra, S.R.; Wang, P.
Downregulation of protein disulfide isomerase in sepsis and its role in tumor necrosis factor-alpha release
Crit. Care Med.
12
R100
2008
Mus musculus, Rattus norvegicus
Reinhardt, C.; von Bruehl, M.L.; Manukyan, D.; Grahl, L.; Lorenz, M.; Altmann, B.; Dlugai, S.; Hess, S.; Konrad, I.; Orschiedt, L.; Mackman, 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.
118
1110-1122
2008
Homo sapiens, Mus musculus
Cho, J.; Furie, B.C.; Coughlin, S.R.; Furie, B.
A critical role for extracellular protein disulfide isomerase during thrombus formation in mice
J. Clin. Invest.
118
1123-1131
2008
Mus musculus
Tian, F.; Zhou, X.; Wikstroem, J.; Karlsson, H.; Sjoeland, H.; Gan, L.M.; Boren, J.; Akyuerek, L.M.
Protein disulfide isomerase increases in myocardial endothelial cells in mice exposed to chronic hypoxia: a stimulatory role in angiogenesis
Am. J. Physiol. Heart Circ. Physiol.
297
H1078-H1086
2009
Homo sapiens, Mus musculus
Hayes, N.V.; Smales, C.M.; Klappa, P.
Protein disulfide isomerase does not control recombinant IgG4 productivity in mammalian cell lines
Biotechnol. Bioeng.
105
770-779
2010
Homo sapiens, Mus musculus
Tamang, D.L.; Alves, B.N.; Elliott, V.; Redelman, D.; Wadhwa, R.; Fraser, S.A.; Hudig, D.
Regulation of perforin lysis: implications for protein disulfide isomerase proteins
Cell. Immunol.
255
82-92
2009
Rattus norvegicus, Mus musculus (P27773), Mus musculus C57BL/6 (P27773)
Okada, K.; Hashimoto, S.; Imaoka, S.
Biological functions of protein disulfide isomerase as a target of phenolic endocrine-disrupting chemicals
J. Health Sci.
56
1-13
2010
Homo sapiens, Mus musculus, Rattus norvegicus
-
Fu, X.M.; Dai, X.; Ding, J.; Zhu, B.T.
Pancreas-specific protein disulfide isomerase has a cell type-specific expression in various mouse tissues and is absent in human pancreatic adenocarcinoma cells: implications for its functions
J. Mol. Histol.
40
189-199
2009
Homo sapiens, Mus musculus
Walker, A.
Protein disulfide isomerase and the endoplasmic reticulum in amyotrophic lateral sclerosis
J. Neurosci.
30
3865-3867
2010
Homo sapiens, Mus musculus, Rattus norvegicus
Park, S.W.; Zhen, G.; Verhaeghe, C.; Nakagami, Y.; Nguyenvu, L.T.; Barczak, A.J.; Killeen, N.; Erle, D.J.
The protein disulfide isomerase AGR2 is essential for production of intestinal mucus
Proc. Natl. Acad. Sci. USA
106
6950-6955
2009
Mus musculus
Hahm, E.; Li, J.; Kim, K.; Huh, S.; Rogelj, S.; Cho, J.
Extracellular protein disulfide isomerase regulates ligand-binding activity of alphaMbeta2 integrin and neutrophil recruitment during vascular inflammation
Blood
121; 3789-800
S1-15
2013
Homo sapiens, Mus musculus
Sobierajska, K.; Skurzynski, S.; Stasiak, M.; Kryczka, J.; Cierniewski, C.S.; Swiatkowska, M.
Protein disulfide isomerase directly interacts with beta-actin Cys374 and regulates cytoskeleton reorganization
J. Biol. Chem.
289
5758-5773
2014
Mus musculus
Okada, K.; Fukui, M.; Zhu, B.T.
Protein disulfide isomerase mediates glutathione depletion-induced cytotoxicity
Biochem. Biophys. Res. Commun.
477
495-502
2016
Mus musculus
EXTERNAL LINKS (specific for EC-Number 5.3.4.1)
Transporter Classification Database (TCDB): 8.A.88.2.3, 8.A.88.2.7
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