Information on EC 5.3.4.1 - protein disulfide-isomerase and Organism(s) Homo sapiens and UniProt Accession Q13087

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Homo sapiens
UNIPROT: Q13087


The expected taxonomic range for this enzyme is: Eukaryota, Bacteria, Archaea


The taxonomic range for the selected organisms is: Homo sapiens

EC NUMBER
COMMENTARY hide
5.3.4.1
-
RECOMMENDED NAME
GeneOntology No.
protein disulfide-isomerase
REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
catalyses the rearrangement of -S-S- bonds in proteins
show the reaction diagram
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
intramolecular oxidoreduction
-
-
-
-
isomerization
-
-
-
-
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 hide
37318-49-3
-
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
physiological function
PDI is a multifunctional protein for catalyzing the formation, isomerization, and reduction of disulfide bonds
malfunction
physiological function
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
creatine kinase
?
show the reaction diagram
-
refolding of creatine kinase, creatine kinase substrate is denatured by 3 M guanidine-HCl, catalysis of creatine kinase refolding by PDI involves disulfide cross-link and dimer to tetramer switch, PDI suppresses aggregation of denatured inactive casein kinase
-
-
?
denatured D-glyceraldehyde-3-phosphate dehydrogenase
refolded D-glyceraldehyde-3-phosphate dehydrogenase
show the reaction diagram
-
chaperone activity of PDI
-
?
denatured rhodanese
?
show the reaction diagram
-
PDI exhibits chaperone activity with rhodanese
-
-
?
E2A homodimer
E2A-basic helix-loop-helix protein heterodimer
show the reaction diagram
-
PDI I and PDI II foster heterodimer formation between E proteins, i.e. basic-loop-helix proteins of the E2A gene products, by a redox mechanism
-
?
envelope glycoprotein 120
envelope glycoprotein 120
show the reaction diagram
-
i.e. human immunodeficiency virus gp120
-
?
estrogen receptor alpha
?
show the reaction diagram
insulin
?
show the reaction diagram
Insulin-(SS) + GSH
Insulin-(SH)2 + GSSG
show the reaction diagram
lactate dehydrogenase
?
show the reaction diagram
-
reactivation of self-aggregated denatured lactate dehydrogenase, guanidine HCl-denatured LDH, chaperone activity, both recombinant wild-type PDI and mutant abb'a' interact with self-aggregated lactate dehydrogenase enhancing LDH reactivation and reducing aggregation
-
-
?
NRCSQGSCWN
NRCSQGSCWN
show the reaction diagram
Proteins
?
show the reaction diagram
Proteins
Proteins
show the reaction diagram
rhodanese
?
show the reaction diagram
-
chaperone activity
-
-
?
riboflavin binding protein
?
show the reaction diagram
-
protein disulfide isomerase and quiescin-sulfhydryl oxidase cooperate in vitro to generate native pairings in substrates ribonuclease A, with four disulfide bonds and 105 disulfide isomers of the fully oxidized protein, and avian riboflavin binding protein, with nine disulfide bonds and more than 34 million corresponding disulfide pairings. The isomerase is not a significant substrate of quiescin-sulfhydryl oxidase. Both reduced RNase and riboflavin binding protein can be efficiently refolded in an aerobic solution containing micromolar concentrations of reduced PDI and nanomolar levels of quiescin-sulfhydryl oxidase without any added oxidized PDI or glutathione redox buffer. In the absence of either quiescin-sulfhydryl oxidase or redox buffer, the fastest refolding of riboflavin binding protein is accomplished with excess reduced PDI and just enough oxidized PDI to generate nine disulfides in the protein client
-
-
?
ribonuclease A
?
show the reaction diagram
-
protein disulfide isomerase and quiescin-sulfhydryl oxidase cooperate in vitro to generate native pairings in ribonuclease A, with four disulfide bonds and 105 disulfide isomers of the fully oxidized protein, and avian riboflavin binding protein, with nine disulfide bonds and more than 34 million corresponding disulfide pairings. The isomerase is not a significant substrate of quiescin-sulfhydryl oxidase. Both reduced RNase and riboflavin binding protein can be efficiently refolded in an aerobic solution containing micromolar concentrations of reduced PDI and nanomolar levels of quiescin-sulfhydryl oxidase without any added oxidized PDI or glutathione redox buffer
-
-
?
RNase A
?
show the reaction diagram
RNase B
?
show the reaction diagram
the ability of the ERp57-calnexin complex to mediate folding of 3H-labeled RNase B is completely dependent on a functional interaction between ERp57 and calnexin, overview
-
-
?
thrombospondin-1 + alpha-thrombin + antithrombin III
thrombospondin-1-S-S-alpha-thrombin-S-S-antithrombin III
show the reaction diagram
-
PDI catalyzes formation of disulfide linked complexes of thrombospondin
-
?
tissue factor
?
show the reaction diagram
unfolded bovine pancreatic trypsin inhibitor
refolded bovine pancreatic trypsin inhibitor
show the reaction diagram
-
-
-
?
unfolded disulfide-bonded protein
refolded disulfide-bonded protein
show the reaction diagram
-
-
-
?
unfolded insulin + reduced glutathione
refolded insulin + oxidized glutathione
show the reaction diagram
-
-
-
?
unfolded proinsulin
refolded proinsulin
show the reaction diagram
-
PDI acts both as a chaperone and as an isomerase during folding and disulfid bond formation of proinsulin, chaperone and isomerization activity is required at the beginning of proinsulin folding, the late refolding process only depends on the isomerase activity
-
?
unfolded RNase
refolded RNase
show the reaction diagram
unfolded RNase A
refolded RNase A
show the reaction diagram
unfolded rRNaSe
refolded rRNase
show the reaction diagram
-
refolding of reduced rRNaSe
-
?
vitronectin + thrombin + antithrombin
vitronectin-thrombin-antithrombin
show the reaction diagram
-
PDI catalyzes the formation of disulfide-linked complexes of vitronectin with thrombin-antithrombin
-
?
additional information
?
-
NATURAL SUBSTRATES
NATURAL PRODUCTS
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
E2A homodimer
E2A-basic helix-loop-helix protein heterodimer
show the reaction diagram
-
PDI I and PDI II foster heterodimer formation between E proteins, i.e. basic-loop-helix proteins of the E2A gene products, by a redox mechanism
-
?
estrogen receptor alpha
?
show the reaction diagram
-
i.e. ERalpha, PDI plays a critical role in estrogen responsiveness by functioning as a molecular chaperone and assisting the receptor in differentially regulating target gene expression, PDI alters estrogen-mediated transactivation, overview, PDI enhances ERalpha-DNA interactions in presence of an oxidizing agent
-
-
?
Insulin-(SS) + GSH
Insulin-(SH)2 + GSSG
show the reaction diagram
Proteins
?
show the reaction diagram
tissue factor
?
show the reaction diagram
-
PDI switches tissue factor from coagulation to signaling by targeting the allosteric Cys186-Cys209 disulfide, the tissue factor coagulant function is enhanced by protein-disulfide isomerase independent of oxidoreductase activity, the chaperone activity is sufficient, PDI enhances factor VIIa-dependent substrate factor X activation 5-10fold in the presence of wild-type, oxidized soluble TF but not TF mutants that contain an unpaired Cys186 or Cys209, PDI has no effect on fully active TF on either negatively charged phospholipids or in activating detergent, indicating that PDI selectively acts upon cryptic TF to facilitate ternary complex formation and macromolecular substrate turnover, overview
-
-
?
additional information
?
-
COFACTOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
glutathione
thioredoxin
-
the enzymes PDI, P5, ERp72, ERp46 and ERp18 contains a thioredoxin binding site and the CGHC active site
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
Ag+
-
PDI binds Ag+
Cu+
-
the enzyme can bind 10 Cu+/mol and form a tetramer
Cu2+
-
PDI binds a maximum of 4 mol Cu2+ and is able to reduce it to Cu+, the bound Cu+ is surface-exposed
Mn2+
-
modulates the thiol isomerase activity of protein disulfide isomerase that is bound to integrin alphaVbeta3 and induces its transition to the ligand-competent state
Zn2+
-
Zn2+ induces dimers/oligomers with decreased isomerase activity
INHIBITORS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
iodoacetamide
alkylation of PDIp by iodoacetamide fully abolishes its enzymatic activity while it still retains most of its chaperone activity
12-O-Tetradecanoylphorbol 13-acetate
-
binds to and moderately inhibits PDI
2-(2-carboxy-4-nitro-phenyl) disulfonyl-5-nitrobenzoic acid
-
i.e. NSC517871. Molecular docking simulation into the redox-active site, residues C37, G38, H39, C40. Inhibitor binds to hydrophobic amino acidsA34, W36, C37, C40, H39, T68 and F80. The redox inhibitory conformations are energetically and statistically favored
2-nitro-5-sulfo-sulfonyl-benzoic acid
-
molecular docking simulation into the redox-active site, residues C37, G38, H39, C40. Inhibitor binds to hydrophobic amino acidsA34, W36, C37, C40, H39, T68 and F80. The redox inhibitory conformations are energetically and statistically favored
2-Nitro-5-thiocyanobenzoic acid
-
molecular docking simulation into the redox-active site, residues C37, G38, H39, C40. Inhibitor binds to hydrophobic amino acidsA34, W36, C37, C40, H39, T68 and F80. The redox inhibitory conformations are energetically and statistically favored
3,3',5-triiodo-L-thyronine
3,3',5-triiodothyronine
-
-
3,4-dichlorophenol
-
inhibits PDI 3,3',5-triiodo-L-thyronine binding activity
4-nonylphenol
-
inhibits PDI 3,3',5-triiodo-L-thyronine binding activity
4-octylphenol
-
inhibits PDI 3,3',5-triiodo-L-thyronine binding activity
5-(3-carboxy-4-nitro-phenyl) sulfonyl-2-nitrobenzoic acid
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i.e. NSC695265. Molecular docking simulation into the redox-active site, residues C37, G38, H39, C40. Inhibitor binds to hydrophobic amino acidsA34, W36, C37, C40, H39, T68 and F80. The redox inhibitory conformations are energetically and statistically favored
anti-PDI Fab fragments
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-
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bacitracin
bacitracin A
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bisphenol A
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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. Inhibits also PDI family members ERp57 and ERp72
Dithionitrobenzoic acid
-
molecular docking simulation into the redox-active site, residues C37, G38, H39, C40. Inhibitor binds to hydrophobic amino acidsA34, W36, C37, C40, H39, T68 and F80. The redox inhibitory conformations are energetically and statistically favored
Estrogens
-
-
-
genistein
-
suppresses binding of proinsulin to PDI, inhibits 66% of PDIs chaperone activity
gentamycin
-
analysis of binding and dissociation constants with PDI and PDI domain deletion mutants
iodoacetamide
-
-
kanamycin
-
analysis of binding and dissociation constants with PDI and PDI domain deletion mutants
MA3 018
-
inhibition of protein disulfide isomerase. Treatment of Mn2+-treated endothelial cells abolishes the conversion of integrin alphaVbeta to the ligand-competent high-affinity state
-
MA3 019
-
inhibition of protein disulfide isomerase. Treatment of Mn2+-treated endothelial cells abolishes the conversion of integrin alphaVbeta to the ligand-competent high-affinity state
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methyl-methanethiosulfonate
-
abolishes PDI oxidoreductase but not chaperone activity
N-ethylmaleimide
-
abolishes PDI oxidoreductase but not chaperone activity
neomycin
-
analysis of binding and dissociation constants with PDI and PDI domain deletion mutants
paromomycin
-
analysis of binding and dissociation constants with PDI and PDI domain deletion mutants
Pentachlorophenol
-
inhibits PDI 3,3',5-triiodo-L-thyronine binding activity
Phenylarsine oxide
-
complete inhibition at 0.01-0.1 mM in vivo
ribostamycin
-
analysis of binding and dissociation constants with PDI and PDI domain deletion mutants
S-nitrosocysteine
-
S-nitrosates endogenous or overexpressed PDI in HEK-293T cells
sisomycin
-
analysis of binding and dissociation constants with PDI and PDI domain deletion mutants
Somatostatin
-
-
streptomycin
-
analysis of binding and dissociation constants with PDI and PDI domain deletion mutants
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
thionitrobenzoic acid
-
molecular docking simulation into the redox-active site, residues C37, G38, H39, C40. Inhibitor binds to hydrophobic amino acidsA34, W36, C37, C40, H39, T68 and F80. The redox inhibitory conformations are energetically and statistically favored
Vancomycin
-
analysis of binding and dissociation constants with PDI and PDI domain deletion mutants
vincristine
-
inhibits chaperone activity but not isomerase activity of both isoforms PDI and P5 in vitro. A 100:1 molar ratio of vincristine to enzyme is sufficient to almost completely inhibit chaperone activity
additional information
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
calnexin
interacts with the enzyme via the b and b' domains, binding site and structure, overview
-
DTT
-
absolutely required for activity
additional information
-
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.028 - 0.063
RNase
-
0.007 - 0.05
RNAse A
-
additional information
additional information
-
light scattering and fluorescence measurement kinetics of wild-type PDI and mutant abb'a' lacking the C-terminal domain c, overview
-
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.000028 - 0.0011
RNase
-
0.017
sRNase
-
-
-
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
8
isomerase assay at
7
assay at
7.4
-
assay at
8
-
assay at
pH RANGE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
4.5 - 7.5
-
approx. 50% of maximal activity at pH 5.5, approx. 75% of maximal activity at pH 7.5
5 - 7
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approx. 50% of maximal activity at pH 5.5, approx. 80% of maximal activity at pH 7.0, oxidation of NRCSQGSCWN
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
25
isomerase assay at
25
-
assay at
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
-
cell surface
Manually annotated by BRENDA team
expression of ERp27
Manually annotated by BRENDA team
expression of ERp27
Manually annotated by BRENDA team
-
-
Manually annotated by BRENDA team
-
cultured, confluent
Manually annotated by BRENDA team
expression of ERp27
Manually annotated by BRENDA team
expression of ERp27
Manually annotated by BRENDA team
-
SV40 transformed, cultured, confluent, weak activity
Manually annotated by BRENDA team
additional information
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
-
in endothelial cells. On activation of endothelial cells, PDI remains confined to the intracellular stores of the dense tubular system and is neither released nor targeted to the cell surface
-
Manually annotated by BRENDA team
additional information
PDB
SCOP
CATH
UNIPROT
ORGANISM
-
-
-
-
-
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
17770
-
MALDI mass spectrometry
27700
x * 27700, ERp27, SDS-PAGE
54000
-
x * 54000, ERP-57
55000
-
x * 55000, SDS-PAGE
56300
-
1 * 56300, calculated from amino acid sequence
57000
-
x * 57000, SDS-PAGE, immunoprecipitation
57700
-
1 * 57700, analytical ultracentrifugation
61200
-
x * 61200, SDS-PAGE under reducing conditions
62000
-
x * 62000, SDS-PAGE
64000
-
1 * 64000, analytical ultracentrifugation
69000
-
light scattering
116000
-
gel filtration, the C-terminal fragment comprising residues 441-491 contributes to the anomalous molecular mass determination by gel filtration
SUBUNITS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
monomer
additional information
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
glutathionylation
-
-
glycoprotein
-
O-linked N-acetyl-D-glucosamine
nitrosylation
-
S-nitrosylation
no glycoprotein
-
-
phosphoprotein
-
-
proteolytic modification
-
-
additional information
Crystallization/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
ERp57 and its isolated bb' and b' domains in complex with the lectin chaperone calnexin, hanging drop vapour diffusion method, equilibration of 14 mg/ml protein in 50 mM Tris-HCl, 0.15 M NaCl, 1 mM DTT, pH 7.5, against 30% w/v PEG 3350, 0.1 M (NH4)2SO4, 0.1 M HEPES buffer, pH 7.5, for 1-3 days at 20°C, X-ray diffraction structure determination and analysis at 2.0 A resoution
hanging drop vapor diffusion method, using 0.01 M zinc chloride, 20% (w/v) polyethylene glycol 6000, and 0.1 M Tris-HCl (pH 8.0)
hanging drop vapor diffusion method, using 0.2 M ammonium sulfate, 0.1 M bis-Tris pH 5.5, 25% (w/v) PEG 3350
hanging-drop vapour-diffusion, mixing of 0.003 ml protein solution i.e. 15 mg/ml protein, 25 mM HEPES, pH 7.5 with 0.003 mL reservoir solution containing 20-23% polyethylene glycol 5000, 200 mM ammonium acetate, 100 mM HEPES, pH 7.5 and 5% glycerol
-
molecular modeling offers a role for the conserved residue R103 in coordinating the oxidative transition-state complex
-
small angle X-ray scattering analysis of purified recombinant wild-type and deletion mutant PDIs, structure modeling, the enzyme forms an approximately flat elliptical cylinder
-
OXIDATION STABILITY
ORGANISM
UNIPROT
LITERATURE
PDI active site can be reduced by glutathion
-
652503
PDI can be reduced by dithiothreitol
-
650995
Purification/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
recombinant wild-type and mutant enzymes from Escherichia coli
from platelet
-
glutathione Sepharose column chromatography
-
glutathione-Sepharose bead chromatography and gel filtration
glutathione-Sepharose resin column chromatography and gel filtration
Ni Sepharose column chromatography
-
Ni-Sepharose column chromatography and Resource Q column chromatography
-
purification from outdated platelets
-
purification of the a domain and the a' domain, expressed in Escherichia coli
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purification of the structural domains and domain combinations expressed in Escherichia coli
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purified from a fibronectin and fibrinogen-rich byproduct of factor VIII production
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recombinant b domain of PDI
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recombinant enzyme
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recombinant GST-tagged bb' fragment and b' fragment from Escherichia coli strain Bl21(DE3) by glutathione affinity chromatography and gel filtration
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recombinant His-tagged enzyme from Escherichia coli strain AD494(DE3) by nickel affinity chromatography
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recombinant His-tagged wild-type and mutant PDIs from Escherichia coli strain M15 by nickel affinity and cation exchange chromatography
-
recombinant His-tagged wild-type and mutant proteins from Escherichia coli strain BL21(DE3) by nickel affinity and anion exchange chromatography
recombinant His-tagged wild-type PDI and mutant abb'a' from Escherichia coli strain BL21(DE3) by nickel affinity and anion exchange chromatography
-
recombinant PDI expressed in Escherichia coli
-
Cloned/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
recombinant expression of wild-type and mutant enzymes in Escherichia coli. Recombinant PDIp protects the Escherichia coli cells against heat shock and oxidative stress-induced cell death independently of its enzymatic activity
sequence comparison
baculovirus expression system
-
cloning of cDNA
-
cloning of the a and a' domain, expression in Escherichia coli
-
expressed in Escherichia coli
-
expressed in Escherichia coli BL21 (DE3) pLysS cells
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expressed in Escherichia coli BL21(DE3) cells
expressed in H-1299 lung cancer cells
-
expression Escherichia coli
-
expression in COS-7 cell
-
expression in COS-7 cells
-
expression in Escherichia coli and Sf9 insect cells
-
expression of enzyme form PDIp in Escherichia coli
-
expression of GST-fusion full-length ERp57 lacking the signal sequence, A24-L505, and the bb', P134-G376, and b', F241-G376, fragments in Escherichia coli strain BL21(DE3)
expression of GST-tagged bb' fragment, residues P135-S357, and of b' fragment, residues L236-S357, in Escherichia coli strain Bl21(DE3)
-
expression of His-tagged enzyme in Escherichia coli strain AD494(DE3)
-
expression of His-tagged wild-type and mutant PDIs in Escherichia coli strain M15
-
expression of His-tagged wild-type PDI and mutant abb'a' lacking the C-terminal domain c in Escherichia coli strain BL21(DE3)
-
expression of myc-tagged mutant PDI in HeLa cells
-
expression of PDI b domain in Escherichia coli
-
expression of protein disulfide isomerase a domain in Escherichia coli
-
expression of the domains and domain combinations in Escherichia coli
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expression of wild-type and mutant ERP-57 in COS-7 cells, co-expression with wild-type and mutant receptors, broken disulfide bond bridge mutant hGnRH receptors and calnexin, interaction analysis, overview
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expression Sf9 insect cells
-
functional complementation of an enzyme-deficient PDI-2-mutant strain of Caenorhabditis elegans, overview
-
PDI, expression of substrate-trapping mutants of PDI family members ERp46, ERp18, ERp57, ERp72, and P5 in HT-1080 cells, the mutant enzymes form mixed disulfides
-
PDI, quantitative expression analysis, overexpression in CHO cells
-
protein disulfide isomerase and the beta-subunit of prolyl 4-hydroxylase, EC 1.14.11.2, are products of the same gene
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recombinant constitutive overexpression in Mus musculus NSC-34 cells and neuroblastoma Neuro2a cells. PDI overexpression decreases mutant SOD1-induced cell death, overview
-
sequence comparison
the gene encoding ERp27 is located at 14,958,241–14,982,750 bp on chromosome 12 and has 7 exons, DNA and amino acid sequence determination and anaylsis, sequence comparison, expression of GFP-fusion ERp27 in COS-7 cell endoplasmic reticulum, expression of N-terminally His-tagged wild-type and mutant ERp57, and of PDI a, b, and b' domains, in Escherichia coli strain BL21(DE3)
transfection of EA.hy926 cells
-
wild-type and/or mutant PDI overexpression in vascular smooth muscle cells and in HEK-293T 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 ALS postmortem tissue
-
protein disulfide isomerase is up-regulated during the unfolded protein response in acute myeloid leukemia. PDI is up-regulated in U-937 cells after induction of endoplasmic reticulum stress
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the enzyme is upregulated in amyotrophic lateral sclerosis
-
ENGINEERING
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
D439A
-
119% of wild-type 4-hydroxylase activity
E231A/W232A/D233G
site-directed mutagenesis, the ERp27 mutant shows a similar structure as wild-type ERp57, but highly reduced binding to ERp57 compared to the wild-type enzyme
E231K
site-directed mutagenesis, the ERp27 mutant shows a similar structure as wild-type ERp57, but highly reduced binding to ERp57 compared to the wild-type enzyme
E454A
-
76% of wild-type 4-hydroxylase activity
F258A
-
strongly reduced binding of DELTA-somatostatin
F258I
-
no binding of DELTA-somatostatin
F258W
-
reduced binding of DELTA-somatostatin
F258W/I272A
-
the mutant shows stronger binding of signal peptide peptidase, SPP, than the wild-type enzyme. PDI F258W/I272A-myc competes with endogenous PDI for SPP and remains attached to SPP, leading to a reduced pool of SPP available for US2-mediated degradation of MHC class I
F299W
-
site-directed mutagenesis, the mutation reduces the interaction between the two chaperones ERP-57 and CANX, but no difference between wild-type and mutant ERP-57 chaperone is observed, even when CANX is additionally transfected, in plasma membrane expression of the enzyme, overview
F449A
-
63% of wild-type 4-hydroxylase activity
F449E
-
9% of wild-type 4-hydroxylase activity
F452R
-
115% of wild-type 4-hydroxylase activity
F454A
-
binds DELTA-somatostatin like wild-type
H278L
-
the mutant protein does not have an appreciable E2-binding activity
I196W
site-directed mutagenesis, the ERp27 mutant shows a structure and ERp57 binding similar to the wild-type enzyme
I272L
-
no binding of DELTA-somatostatin
I272N
-
no binding of DELTA-somatostatin
I272Q
-
no binding of DELTA-somatostatin
I272W
-
no binding of DELTA-somatostatin
I438E
-
79% of wild-type 4-hydroxylase activity
K246A
-
reduced binding of DELTA-somatostatin
K259A
-
binds DELTA-somatostatin like wild-type
K274A
site-directed mutagenesis, the mutant shows affected interaction with calnexin
K332A
site-directed mutagenesis, the mutant shows binding affinity with calnexin identical to wild-type enzyme
K451A
-
74% of wild-type 4-hydroxylase activity
L242A
-
binds DELTA-somatostatin like wild-type
L242T
-
strongly reduced binding of DELTA-somatostatin
L244A
-
reduced binding of DELTA-somatostatin
L244W
-
strongly reduced binding of DELTA-somatostatin
L255A
-
binds DELTA-somatostatin like wild-type
L255R
-
reduced binding of DELTA-somatostatin
L343A
-
the mutant is more sensitive to proteinase K than wild type enzyme. The mutant shows the same chaperone activity as that of wild type PDI
L446E
-
107% of wild-type 4-hydroxylase activity
P245K
-
no full length protein
Q265L
-
the mutant displays similar E2-binding activity as the corresponding wild type proteins
Q265L/H278L
-
the mutant protein does not have any E2-binding activity
R120D
-
less than 2% of wild-type activity in NRCSQGSCWN oxidation assay
R120K
-
71% of wild-type activity in NRCSQGSCWN oxidation assay
R120Q
-
26% of wild-type activity in NRCSQGSCWN oxidation assay
R120S
-
40% of wild-type activity in NRCSQGSCWN oxidation assay
R280A
site-directed mutagenesis, the mutant shows a structure reduced binding of ERp27, wild-type and mutants, as compared to the wild-type ERp57
R282A
site-directed mutagenesis, the mutant shows affected interaction with calnexin
S249A
-
reduced binding of DELTA-somatostatin
S249K
-
binds DELTA-somatostatin like wild-type
S256D
-
reduced binding of DELTA-somatostatin
V220I
-
binds DELTA-somatostatin like wild-type
V437D
-
102% of wild-type 4-hydroxylase activity
W128F
-
95% of wild-type activity in NRCSQGSCWN oxidation assay
additional information
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
analysis
-
development of a method to determine quantitatively the redox state of active-site cysteines found in the Cys-Xaa-Xaa-Cys motif in living cells. Method is based on the alkylation of cysteines by methoxy polyethylene glycol 5000 maleimide. In vivo, protein disulfide isomerase is present in two semi-oxidized forms in which either the first active site in the a domain or the second active site in the a' domain is oxidized. In HEK-293 cells, about 50% of enzyme is fully reduced, in 18% a domain is oxidized, a' reduced, in 15%, the a domain is reduced, a' oxidized, and 16% of enzyme are fully oxidized
diagnostics
-
the absence of PDIp expression in pancreatic adenocarcinoma may serve as an additional biomarker for pancreatic cancer
medicine
pharmacology
-
protein disulfide isomerase is a potential therapeutic target in amyotrophic lateral sclerosis and (+-)-trans-1,2-bis(mercaptoacetamido)cyclohexane and other molecular mimics of protein disulfide isomerase could be of benefit in amyotrophic lateral sclerosis and other neurodegenerative diseases related to protein misfolding