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Gene Review

PADI1  -  peptidyl arginine deiminase, type I

Homo sapiens

Synonyms: HPAD10, PAD1, PDI, PDI1, Peptidylarginine deiminase I, ...
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Disease relevance of PADI1

  • Furthermore, we demonstrate that human cytomegalovirus US3 protein inhibits CD8(+) T cell recognition by mediating PDI degradation, verifying the functional relevance of PDI-catalyzed peptide editing in controlling intracellular pathogens [1].
  • To assess the role of PDI in the cellular action of NO, we inhibited human erythroleukemia (HEL) cell-surface PDI expression using an antisense phosphorothioate oligodeoxynucleotide directed against PDI mRNA [2].
  • We report here on the expression in baculovirus vectors of various mutant PDI/beta-subunits together with a wild-type alpha-subunit of the human prolyl 4-hydroxylase alpha 2 beta 2 tetramer in Spodoptera frugiperda insect cells [3].
  • The deduced amino acid sequence of B2 was also 35% identical to that of a rat form I phosphatidylinositol-specific phospholipase C. Lysates from Escherichia coli cells harboring an expression plasmid bearing the B2 sequence contained significantly elevated levels of PDI activity [4].
  • The results imply that HIV and its target cell engage in a thiol-disulfide interchange mediated by PDI and that the reduction of critical disulfides in viral envelope glycoproteins may be the initial event that triggers conformational changes required for HIV entry and cell infection [5].

Psychiatry related information on PADI1

  • The influence of the replacement of methyl groups in the alpha-position of the N atom in cyclic alkoxyamines by larger ethyl groups on the styrene polymerization (reaction time, PDI, kinetics of the C-O bond homolysis) is discussed [6].
  • A total of 444 healthy individuals completed the 21-item PDI and two other questionnaires measuring florid delusions and social desirability [7].
  • Interestingly, we found overexpressed protein disufide isomerase (PDI) in brains of sporadic Creutzfeldt-Jakob disease (sCJD, human prion disease) patients using two dimensional electrophoresis and Western blot analysis but not in other neurodegenerative disorders as Down Syndrome and Alzheimer's disease [8].
  • Mental and psychomotor developmental indices (MDI, PDI) were determined with the Bayley Scales of Infant Development I: > or = -1 S.D.: normal, -2 to -1 S.D.: moderate delay and < -2 S.D.: severe delay [9].
  • METHOD: Eighty-one patients diagnosed with a mental disorder with psychotic features (schizophrenia, schizoaffective disorder, bipolar disorder, major depression) and 210 putatively healthy individuals were invited to complete the PDI and the brief version of the General Health Questionnaire (GHQ-12) [10].

High impact information on PADI1

  • We used a case-control linkage disequilibrium study to show that PADI type 4 is a susceptibility locus for rheumatoid arthritis (P = 0.000008) [11].
  • In the endoplasmic reticulum of eukaryotes, disulfide formation is catalyzed by protein disulfide isomerase (PDI); by contrast, prokaryotes produce a family of disulfide bond (Dsb) proteins, which together achieve an equivalent outcome in the bacterial periplasm [12].
  • This oligodeoxynucleotide decreased cell-surface PDI content by 74.1 +/- 9.3% and PDI folding activity by 46.6 +/- 3.5% compared with untreated or "scrambled" phosphorothioate oligodeoxynucleotide-treated cells (P < 0.0001) [2].
  • This decrease in cell-surface PDI was associated with a significant decrease in cyclic guanosine monophosphate (cGMP) generation after S-nitrosothiol exposure (65.4 +/- 26.7% reduction compared with control; P < 0.05), with no effect on cyclic adenosine monophosphate (cAMP) generation after prostaglandin E1 exposure [2].
  • The active site of PDI closely resembles that of the redox protein thioredoxin, and cDNA cloning has revealed a superfamily of proteins with related active-site sequences, in organisms ranging from bacteria to higher animals and plants [13].

Chemical compound and disease context of PADI1

  • We provide evidence that the same reductive process plays a role in the penetration of membrane-bound human immunodeficiency virus (HIV) and show that HIV infection of human lymphoid cells is markedly inhibited by the membrane-impermeant sulfhydryl blocker 5,5'-dithiobis(2-nitrobenzoic acid), by bacitracin, and by anti-PDI antibodies [5].
  • We examined the consequence of over- or underexpression of PDI in HT1080 fibrosarcoma cells for the redox state of cell-surface protein thiols/disulfides [14].
  • Human PDI was expressed to the Escherichia coli periplasm, by using a plasmid encoded ompA-PDI fusion under the control of the trp promoter [15].
  • The dithiol/disulfide active sites of each of the two isolated thioredoxin-like domains of protein disulfide isomerase (PDI) expressed in Escherichia coli have been characterized in order to understand their catalytic mechanisms and their functions in PDI [16].
  • However, the cell-surface thiol-reactive reagent 5, 5'-dithiobis(2-nitrobenzoic acid) (DTNB) had a much stronger inhibitory effect in our system, suggesting that cell-surface thiol-containing molecules other than PDI, acting alone or in concert, have a greater effect than PDI on HIV-1 Env-mediated fusion [17].

Biological context of PADI1

  • We identified a total of 87 single nucleotide polymorphisms (SNPs) in PADI1 and PADI3 gene loci [18].
  • We also identified two insertion-deletion polymorphisms in introns of the PADI1 [18].
  • Following a comparison of our data with SNPs in the dbSNP database in the National Center for Biotechnology Information, 45 SNPs are considered to be novel: 33 were identified in the PADI1 gene locus and 12 in the PADI3 gene locus [18].
  • This study is the first description of the human PADI6 gene and encoded protein, and the first step towards a better understanding of the coordinated regulation of PADI gene expression [19].
  • Genetic factors such as a gene polymorphism of the citrullinating enzyme, PADI, might be associated with the breakage of self-tolerance and induction of autoimmunity against citrullinated proteins [20].

Anatomical context of PADI1

  • The role of protein disulphide isomerase (PDI) and other resident proteins of the endoplasmic reticulum (ER) lumen in co- and post-translational modification of secretory proteins has been studied in experiments on translation in vitro [21].
  • When saponin-washed microsomal membranes were reconstituted with homogeneous protein disulphide isomerase (PDI), the generated vesicles gave the same pattern of co-translationally glycosylated IFN-gamma as saponin-washed microsomal membranes lacking PDI [21].
  • In this report, we identify four positive regulatory domains (PDI to PDIV) in the E-selectin promoter that are required for maximal levels of TNF-alpha induction in endothelial cells [22].
  • Other blood cells showed little PDI [23].
  • Both domains were secreted, however, from a stable cell line expressing a secreted form of PDI lacking its ER retrieval signal [24].

Associations of PADI1 with chemical compounds

  • Protein disulfide isomerase (PDI) markedly increases the reactivation yield and prevents the aggregation of APLA2 during refolding in a redox buffer containing GSH and GSSG [25].
  • More recently it was found that the same membrane function can be inhibited by bacitracin, an inhibitor of protein disulfide-isomerase (PDI), and by monoclonal antibodies against PDI, suggesting that PDI catalyzes a thiol-disulfide interchange between its thiols and the disulfides of membrane-bound macromolecules [5].
  • The polypeptide encoded by a clone designated B2 consisted of 512 amino acids and was characterized by a 24-amino acid hydrophobic leader sequence, two regions with absolute identity to the vertebrate PDI active site (Ala-Pro-Trp-Cys-Gly-His-Cys-Lys), and a C-terminal endoplasmic reticulum retention signal (Lys-Asp-Glu-Leu) [4].
  • A series of donor-bridge-acceptor molecules having phenothiazine (PTZ) donors, 2,7-oligofluorene (FL(n)) bridges, and perylene-3,4:9,10-bis(dicarboximide) (PDI) acceptors was studied [26].
  • Using the membrane-impermeant sulfhydryl blocker para-chloromercuriphenyl sulfonate, the inhibitor of disulfide exchange bacitracin, and the monoclonal anti-PDI antibody RL90, we examined fibrinogen binding to alpha(IIb)beta(3) as well as ligation-induced allosteric changes in the conformation of alpha(IIb)beta(3) [27].

Analytical, diagnostic and therapeutic context of PADI1

  • Permeabilized platelets showed little cytosolic PDI by indirect immunofluorescence microscopy, suggesting that the majority of platelet PDI is localized to the platelet surface [23].
  • In this study, antibodies against PDI were used to show PDI antigen on the platelet surface by indirect immunofluorescence microscopy and by flow cytometry [23].
  • We show that PDI is strongly expressed on invasive glioma cells, in both xenografts and at the invasive front of human glioblastomas [28].
  • Western blot analysis revealed that both immunoglobulins and PDI protein were expressed in the coinfected cells [29].
  • Immunoprecipitation with anti-PDI antibody revealed that heterologous PDI-C and PDI-NC were insoluble, even though PDI-N and wild-type PDI protein were detected in soluble form [29].


  1. Redox Regulation Facilitates Optimal Peptide Selection by MHC Class I during Antigen Processing. Park, B., Lee, S., Kim, E., Cho, K., Riddell, S.R., Cho, S., Ahn, K. Cell (2006) [Pubmed]
  2. Cell-surface protein disulfide isomerase catalyzes transnitrosation and regulates intracellular transfer of nitric oxide. Zai, A., Rudd, M.A., Scribner, A.W., Loscalzo, J. J. Clin. Invest. (1999) [Pubmed]
  3. Site-directed mutagenesis of human protein disulphide isomerase: effect on the assembly, activity and endoplasmic reticulum retention of human prolyl 4-hydroxylase in Spodoptera frugiperda insect cells. Vuori, K., Pihlajaniemi, T., Myllylä, R., Kivirikko, K.I. EMBO J. (1992) [Pubmed]
  4. Molecular cloning of a putative plant endomembrane protein resembling vertebrate protein disulfide-isomerase and a phosphatidylinositol-specific phospholipase C. Shorrosh, B.S., Dixon, R.A. Proc. Natl. Acad. Sci. U.S.A. (1991) [Pubmed]
  5. Inhibition of human immunodeficiency virus infection by agents that interfere with thiol-disulfide interchange upon virus-receptor interaction. Ryser, H.J., Levy, E.M., Mandel, R., DiSciullo, G.J. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  6. Steric and electronic effects in cyclic alkoxyamines--synthesis and applications as regulators for controlled/living radical polymerization. Wetter, C., Gierlich, J., Knoop, C.A., Müller, C., Schulte, T., Studer, A. Chemistry (Weinheim an der Bergstrasse, Germany) (2004) [Pubmed]
  7. Measuring delusional ideation: the 21-item Peters et al. Delusions Inventory (PDI). Peters, E., Joseph, S., Day, S., Garety, P. Schizophrenia bulletin. (2004) [Pubmed]
  8. Overexpressed protein disulfide isomerase in brains of patients with sporadic Creutzfeldt-Jakob disease. Yoo, B.C., Krapfenbauer, K., Cairns, N., Belay, G., Bajo, M., Lubec, G. Neurosci. Lett. (2002) [Pubmed]
  9. Developmental outcome at 18 and 24 months of age in very preterm children: a cohort study from 1996 to 1997. Stoelhorst, G.M., Rijken, M., Martens, S.E., van Zwieten, P.H., Feenstra, J., Zwinderman, A.H., Wit, J.M., Veen, S. Early Hum. Dev. (2003) [Pubmed]
  10. The psychometric discriminative properties of the Peters et al Delusions Inventory: a receiver operating characteristic curve analysis. Preti, A., Rocchi, M.B., Sisti, D., Mura, T., Manca, S., Siddi, S., Petretto, D.R., Masala, C. Comprehensive psychiatry (2007) [Pubmed]
  11. Functional haplotypes of PADI4, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with rheumatoid arthritis. Suzuki, A., Yamada, R., Chang, X., Tokuhiro, S., Sawada, T., Suzuki, M., Nagasaki, M., Nakayama-Hamada, M., Kawaida, R., Ono, M., Ohtsuki, M., Furukawa, H., Yoshino, S., Yukioka, M., Tohma, S., Matsubara, T., Wakitani, S., Teshima, R., Nishioka, Y., Sekine, A., Iida, A., Takahashi, A., Tsunoda, T., Nakamura, Y., Yamamoto, K. Nat. Genet. (2003) [Pubmed]
  12. Protein disulfide isomerase: the structure of oxidative folding. Gruber, C.W., Cemazar, M., Heras, B., Martin, J.L., Craik, D.J. Trends Biochem. Sci. (2006) [Pubmed]
  13. Protein disulphide isomerase: building bridges in protein folding. Freedman, R.B., Hirst, T.R., Tuite, M.F. Trends Biochem. Sci. (1994) [Pubmed]
  14. Redox control of exofacial protein thiols/disulfides by protein disulfide isomerase. Jiang, X.M., Fitzgerald, M., Grant, C.M., Hogg, P.J. J. Biol. Chem. (1999) [Pubmed]
  15. Human protein disulfide isomerase functionally complements a dsbA mutation and enhances the yield of pectate lyase C in Escherichia coli. Humphreys, D.P., Weir, N., Mountain, A., Lund, P.A. J. Biol. Chem. (1995) [Pubmed]
  16. Characterization of the active site cysteine residues of the thioredoxin-like domains of protein disulfide isomerase. Darby, N.J., Creighton, T.E. Biochemistry (1995) [Pubmed]
  17. Role of protein disulfide isomerase and other thiol-reactive proteins in HIV-1 envelope protein-mediated fusion. Ou, W., Silver, J. Virology (2006) [Pubmed]
  18. Identification of 45 novel SNPs in the 83-kb region containing peptidylarginine deiminase types 1 and 3 loci on chromosomal band 1p36.13. Iida, A., Nakamura, Y. J. Hum. Genet. (2004) [Pubmed]
  19. Comparative analysis of the mouse and human peptidylarginine deiminase gene clusters reveals highly conserved non-coding segments and a new human gene, PADI6. Chavanas, S., Méchin, M.C., Takahara, H., Kawada, A., Nachat, R., Serre, G., Simon, M. Gene (2004) [Pubmed]
  20. Clinical significance of anti-CCP antibodies in rheumatoid arthritis. Mimori, T. Intern. Med. (2005) [Pubmed]
  21. Cotranslational glycosylation of proteins in systems depleted of protein disulphide isomerase. Bulleid, N.J., Freedman, R.B. EMBO J. (1990) [Pubmed]
  22. A striking similarity in the organization of the E-selectin and beta interferon gene promoters. Whitley, M.Z., Thanos, D., Read, M.A., Maniatis, T., Collins, T. Mol. Cell. Biol. (1994) [Pubmed]
  23. Localization of protein disulfide isomerase to the external surface of the platelet plasma membrane. Essex, D.W., Chen, K., Swiatkowska, M. Blood (1995) [Pubmed]
  24. Quality control in the endoplasmic reticulum: PDI mediates the ER retention of unassembled procollagen C-propeptides. Bottomley, M.J., Batten, M.R., Lumb, R.A., Bulleid, N.J. Curr. Biol. (2001) [Pubmed]
  25. Both the isomerase and chaperone activities of protein disulfide isomerase are required for the reactivation of reduced and denatured acidic phospholipase A2. Yao, Y., Zhou, Y., Wang, C. EMBO J. (1997) [Pubmed]
  26. Wire-like charge transport at near constant bridge energy through fluorene oligomers. Goldsmith, R.H., Sinks, L.E., Kelley, R.F., Betzen, L.J., Liu, W., Weiss, E.A., Ratner, M.A., Wasielewski, M.R. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  27. Sustained integrin ligation involves extracellular free sulfhydryls and enzymatically catalyzed disulfide exchange. Lahav, J., Jurk, K., Hess, O., Barnes, M.J., Farndale, R.W., Luboshitz, J., Kehrel, B.E. Blood (2002) [Pubmed]
  28. Protein disulfide isomerase expression is related to the invasive properties of malignant glioma. Goplen, D., Wang, J., Enger, P.?.?., Tysnes, B.B., Terzis, A.J., Laerum, O.D., Bjerkvig, R. Cancer Res. (2006) [Pubmed]
  29. Thioredoxin domain non-equivalence and anti-chaperone activity of protein disulfide isomerase mutants in vivo. Whiteley, E.M., Hsu, T.A., Betenbaugh, M.J. J. Biol. Chem. (1997) [Pubmed]
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