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Gene Review

PDIA3  -  protein disulfide isomerase family A,...

Homo sapiens

Synonyms: 58 kDa glucose-regulated protein, 58 kDa microsomal protein, Disulfide isomerase ER-60, ER protein 57, ER protein 60, ...
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Disease relevance of PDIA3

  • Amounts of calreticulin and PDIA3 fragments were also significantly different between patients with HCC and at-risk patients (patients with chronic hepatitis or cirrhosis) [1].
  • ERp57 had three major protease-sensitive regions, the first of which was located between residues 120 and 150, the second between 201 and 215, and the third between 313 and 341, the data thus being consistent with a four-domain structure abb'a'. Recombinant expression in Escherichia coli was used to verify the domain boundaries [2].
  • Likewise, excess exogenous recombinant human GRP58 prepared using a baculovirus expression system preferentially inhibited Stat3 DNA-binding activity in the S100 cytosol, suggesting that GRP58 may sequester activated Stat3 [3].
  • Characterization of the p68/p58 heterodimer of human immunodeficiency virus type 2 reverse transcriptase [4].
  • The p68/p58 HIV-2 RT heterodimer, produced by specific cleavage using HIV-2 protease, should be useful for inhibition and biophysical studies aimed at discovering and designing drugs directed toward HIV-2 [4].

High impact information on PDIA3


Biological context of PDIA3

  • We previously showed that the major histocompatibility complex (MHC) class I chaperone tapasin can be detected as a mixed disulfide with the thiol-oxidoreductase ERp57 [8].
  • Tapasin upregulation by interferon-gamma induces sequestration of the vast majority of ERp57 into the MHC class I peptide-loading complex [8].
  • The primary substrate binding site in the b' domain of ERp57 is adapted for endoplasmic reticulum lectin association [9].
  • Heavy chains were also isolated from Raji cells in multimolecular complexes (peptide loading complexes) containing the transporter associated with antigen processing, tapasin and ERp57 with and without the lectin-like folding chaperone, calreticulin [10].
  • We also isolated an intronless ERp60 gene that probably represents a pseudogene [11].

Anatomical context of PDIA3


Associations of PDIA3 with chemical compounds

  • The formation of at least one of the disulfide bonds in the CD1d heavy chain is coupled to its glucose trimming-dependent association with ERp57, calnexin, and calreticulin [14].
  • It was speculated that ERp57 is a generic component of the glycan-dependent ER quality control system [15].
  • Furthermore, ERp57 was shown to efficiently catalyze disulfide reduction, disulfide isomerization, and dithiol oxidation in substrate proteins [12].
  • In contrast to reports on the activities of nonhuman forms of P58, the purified expressed human P58 showed no carnitine acyltransferase or protease activities [16].
  • HCP association was dependent on tyrosine phosphorylation of p58 [7].

Physical interactions of PDIA3

  • In addition, we report that ERp27 is bound by ERp57 both in vitro and in vivo by a similar mechanism by which ERp57 binds calreticulin [17].
  • Using EMSA, DNA affinity experiments, and chromatin immunoprecipitation, STAT3 was found in M14 to bind the alpha2-macroglobulin gene enhancer in association with the protein disulfide isomerase isoform ERp57 [18].
  • The K(D) value of PDI binding to ERp57 was calculated as 5.46x10(-6)M with the BIACORE system [19].
  • No direct binding of monoglucosylated ribonuclease B or monoglucosylated glycans to ERp57 could be detected, but we show that ERp57 interacts directly with calnexin [20].

Regulatory relationships of PDIA3

  • Interestingly, low concentrations of ERp57 enhanced the chaperone activity of PDI, while high concentrations interfered with chaperone activity [19].

Other interactions of PDIA3

  • ERp57 is a member of the protein disulfide isomerase (PDI) family that is located in the endoplasmic reticulum (ER) and characterized by its specificity for glycoproteins [9].
  • Noncovalent interactions between the native proteins inhibit the reductase activity of the thioredoxin CXXC motif within the N-terminal a domain of ERp57 to maintain its interaction with tapasin [8].
  • Considering the functional association of the two proteins, the overexpression of ERp57 observed in a variety of transformed cells might be relevant to the oncogenic properties of STAT3 [18].
  • The inhibitory effect mediated by CD94 molecules on NK cytolytic activity is lower in magnitude than that of bona fide inhibitory receptors such as p58 or p70 [21].
  • Using differential sedimentation and density equilibrium flotation methods, Stat3 and GRP58 were observed to be coassociated with cytoplasmic membranes enriched for the plasma membrane marker 5' nucleotidase but not with those containing the endoplasmic reticulum marker BiP/GRP78 [3].

Analytical, diagnostic and therapeutic context of PDIA3

  • The ERp60 gene was mapped by fluorescence in situ hybridization to 15q15 and the processed gene to 1q21, so that neither was located on the same chromosome as the human PDI and thioredoxin genes [11].
  • One main band observed using SDS-PAGE was identified as ERp57 (one of the PDI family proteins) by LC-MS/MS analysis [19].
  • Both cytosolic Stat3 and GRP58 eluted during Superose-6 gel-filtration chromatography in complexes of size 200-400 kDa (statosome I), and anti-Stat3 pAb cross-immunoprecipitated GRp58 from these FPLC elution fractions [3].
  • In the present study, the association between GRP58 and Stat3 in different cytoplasmic compartments was evaluated using cross-immunoprecipitation and cell-fractionation techniques [3].
  • Immunoprecipitation showed that a number of proteins are associated with MHC-I heavy chains at the surface of activated T cells, including the CD8alphabeta receptor and the chaperone tandem calreticulin/ERp57, associations that rely upon the existence of a pool of HC-10-reactive molecules [22].


  1. Cleavage of endoplasmic reticulum proteins in hepatocellular carcinoma: Detection of generated fragments in patient sera. Chignard, N., Shang, S., Wang, H., Marrero, J., Bréchot, C., Hanash, S., Beretta, L. Gastroenterology (2006) [Pubmed]
  2. Identification and characterization of structural domains of human ERp57: association with calreticulin requires several domains. Silvennoinen, L., Myllyharju, J., Ruoppolo, M., Orrù, S., Caterino, M., Kivirikko, K.I., Koivunen, P. J. Biol. Chem. (2004) [Pubmed]
  3. Association of the chaperone glucose-regulated protein 58 (GRP58/ER-60/ERp57) with Stat3 in cytosol and plasma membrane complexes. Guo, G.G., Patel, K., Kumar, V., Shah, M., Fried, V.A., Etlinger, J.D., Sehgal, P.B. J. Interferon Cytokine Res. (2002) [Pubmed]
  4. Characterization of the p68/p58 heterodimer of human immunodeficiency virus type 2 reverse transcriptase. Fan, N., Rank, K.B., Poppe, S.M., Tarpley, W.G., Sharma, S.K. Biochemistry (1996) [Pubmed]
  5. Molecular cloning and complete amino-acid sequence of form-I phosphoinositide-specific phospholipase C. Bennett, C.F., Balcarek, J.M., Varrichio, A., Crooke, S.T. Nature (1988) [Pubmed]
  6. Interaction of the thiol-dependent reductase ERp57 with nascent glycoproteins. Oliver, J.D., van der Wal, F.J., Bulleid, N.J., High, S. Science (1997) [Pubmed]
  7. Recruitment of tyrosine phosphatase HCP by the killer cell inhibitor receptor. Burshtyn, D.N., Scharenberg, A.M., Wagtmann, N., Rajagopalan, S., Berrada, K., Yi, T., Kinet, J.P., Long, E.O. Immunity (1996) [Pubmed]
  8. Tapasin and ERp57 form a stable disulfide-linked dimer within the MHC class I peptide-loading complex. Peaper, D.R., Wearsch, P.A., Cresswell, P. EMBO J. (2005) [Pubmed]
  9. The primary substrate binding site in the b' domain of ERp57 is adapted for endoplasmic reticulum lectin association. Russell, S.J., Ruddock, L.W., Salo, K.E., Oliver, J.D., Roebuck, Q.P., Llewellyn, D.H., Roderick, H.L., Koivunen, P., Myllyharju, J., High, S. J. Biol. Chem. (2004) [Pubmed]
  10. Identification of specific glycoforms of major histocompatibility complex class I heavy chains suggests that class I peptide loading is an adaptation of the quality control pathway involving calreticulin and ERp57. Radcliffe, C.M., Diedrich, G., Harvey, D.J., Dwek, R.A., Cresswell, P., Rudd, P.M. J. Biol. Chem. (2002) [Pubmed]
  11. Structures of the human gene for the protein disulfide isomerase-related polypeptide ERp60 and a processed gene and assignment of these genes to 15q15 and 1q21. Koivunen, P., Horelli-Kuitunen, N., Helaakoski, T., Karvonen, P., Jaakkola, M., Palotie, A., Kivirikko, K.I. Genomics (1997) [Pubmed]
  12. ERp57 is a multifunctional thiol-disulfide oxidoreductase. Frickel, E.M., Frei, P., Bouvier, M., Stafford, W.F., Helenius, A., Glockshuber, R., Ellgaard, L. J. Biol. Chem. (2004) [Pubmed]
  13. In cerebrospinal fluid ER chaperones ERp57 and calreticulin bind beta-amyloid. Erickson, R.R., Dunning, L.M., Olson, D.A., Cohen, S.J., Davis, A.T., Wood, W.G., Kratzke, R.A., Holtzman, J.L. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  14. Calnexin, calreticulin, and ERp57 cooperate in disulfide bond formation in human CD1d heavy chain. Kang, S.J., Cresswell, P. J. Biol. Chem. (2002) [Pubmed]
  15. The thiol oxidoreductase ERp57 is a component of the MHC class I peptide-loading complex. Hughes, E.A., Cresswell, P. Curr. Biol. (1998) [Pubmed]
  16. cDNA cloning and baculovirus expression of the human liver endoplasmic reticulum P58: characterization as a protein disulfide isomerase isoform, but not as a protease or a carnitine acyltransferase. Bourdi, M., Demady, D., Martin, J.L., Jabbour, S.K., Martin, B.M., George, J.W., Pohl, L.R. Arch. Biochem. Biophys. (1995) [Pubmed]
  17. ERp27, a New Non-catalytic Endoplasmic Reticulum-located Human Protein Disulfide Isomerase Family Member, Interacts with ERp57. Alanen, H.I., Williamson, R.A., Howard, M.J., Hatahet, F.S., Salo, K.E., Kauppila, A., Kellokumpu, S., Ruddock, L.W. J. Biol. Chem. (2006) [Pubmed]
  18. ERp57 is present in STAT3-DNA complexes. Eufemi, M., Coppari, S., Altieri, F., Grillo, C., Ferraro, A., Turano, C. Biochem. Biophys. Res. Commun. (2004) [Pubmed]
  19. ERp57 binds competitively to protein disulfide isomerase and calreticulin. Kimura, T., Imaishi, K., Hagiwara, Y., Horibe, T., Hayano, T., Takahashi, N., Urade, R., Kato, K., Kikuchi, M. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  20. Enhanced catalysis of ribonuclease B folding by the interaction of calnexin or calreticulin with ERp57. Zapun, A., Darby, N.J., Tessier, D.C., Michalak, M., Bergeron, J.J., Thomas, D.Y. J. Biol. Chem. (1998) [Pubmed]
  21. CD94 functions as a natural killer cell inhibitory receptor for different HLA class I alleles: identification of the inhibitory form of CD94 by the use of novel monoclonal antibodies. Sivori, S., Vitale, M., Bottino, C., Marcenaro, E., Sanseverino, L., Parolini, S., Moretta, L., Moretta, A. Eur. J. Immunol. (1996) [Pubmed]
  22. Misfolding of major histocompatibility complex class I molecules in activated T cells allows cis-interactions with receptors and signaling molecules and is associated with tyrosine phosphorylation. Santos, S.G., Powis, S.J., Arosa, F.A. J. Biol. Chem. (2004) [Pubmed]
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