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Gene Review

Pdia3  -  protein disulfide isomerase associated 3

Mus musculus

Synonyms: 58 kDa glucose-regulated protein, 58 kDa microsomal protein, 58kDa, Disulfide isomerase ER-60, ER protein 57, ...
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Disease relevance of Pdia3


High impact information on Pdia3

  • Death in utero caused by ubiquitous ERp57 deletion was prevented by specific deletion in the B cell compartment [6].
  • The thiol-oxidoreductase ERp57 is an integral component of the peptide-loading complex of the major histocompatibility complex (MHC) class I pathway, but its function is unknown [6].
  • To investigate its function in antigen presentation, we generated ERp57-deficient mice [6].
  • Interestingly, cholera toxin, another toxic agent that crosses the ER membrane into the cytosol, is unfolded by PDI in the ER [7].
  • Peptide assembly involves several novel cofactors - including the proteins tapasin and ERp57, which may be important for stabilisation of empty class I molecules as well as quality control after peptide binding [8].

Biological context of Pdia3


Anatomical context of Pdia3

  • Deconvolution microscopy using fluorescently labeled virus and cellular markers showed that virus reaches the endoplasmic reticulum (ER) normally in cells with reduced PDI but subsequently fails to exit the ER [1].
  • In addition, the pituitary gland PDI mRNA was 2- to 3-fold higher in 10-day-old mice than in adults [9].
  • Furthermore, a high correlation was observed between intracellular amounts of ERp61 and immunoglobulin production by hybridoma cells [11].
  • The ER location of the protein in fibroblasts was immunocytochemically confirmed by double staining for ERp61 and another ER-resident protein, PDI or Hsp47 [11].
  • A role for sperm surface protein disulfide isomerase activity in gamete fusion: evidence for the participation of ERp57 [12].

Associations of Pdia3 with chemical compounds

  • Although the Glu(239), Asp(241), and Glu(243) mutants did not bind ERp57 efficiently, they fully restored bradykinin-dependent Ca2+ release in crt(-/-) cells [13].
  • While only small amounts of the total GRP78, PDI and Crt molecules exist on the cell surface at steady state, a significant fraction of the newly synthesized molecules are transported to the cell surface and transport of these proteins is inhibited by treatment with brefeldin A [14].
  • Posttranslational inhibition of glucose excision prolonged association of H2a precursor to calnexin but not to ERp57 [15].
  • This low concentration of castanospermine accelerated the degradation of H2a, suggesting that ERp57 protects the glycoprotein from degradation and not calnexin [15].
  • Bacterially expressed recombinant ERp57/GRP58 protein contained a thiol-dependent reductase activity which was completely abolished when Ser residues were substituted for Cys residues in both of the two motifs [16].

Physical interactions of Pdia3

  • However, H2b, which will exit to the Golgi, dissociated from calnexin and remained bound for a longer period to ERp57, whereas the opposite was true for the endoplasmic reticulum-associated degradation substrate H2a that will go to the endoplasmic reticulum-derived quality control compartment [15].

Co-localisations of Pdia3


Regulatory relationships of Pdia3


Other interactions of Pdia3

  • We identified four amino acid residues (Glu(239), Asp(241), Glu(243), and Trp(244)) at the hairpin tip of the P-domain that are critical in the formation of a complex between ERp57 and calreticulin [13].
  • The ERp61 and ERp72 mRNAs were present at 2- to 3-fold higher levels in the pituitary glands of the 10- and 22-day-old mice, than in the adult mice [9].
  • Depletion of ERp57 by RNA interference delayed heavy chain disulfide bond formation, slowed folding of the heavy chain alpha(3) domain, and caused slight delays in the transport of class I molecules from the endoplasmic reticulum to the Golgi apparatus [10].
  • Seventy percent of IgA receptor activity is lost when T560 is treated with PI-PLC; part of this loss of activity is due to activation of PKC and is inhibited by staurosporine, but approximately 30% of it is not protected by staurosporine indicating that some, or all, of the IgA receptor of T560 is connected to the cell membrane via a GPI linker [17].
  • These two proteins were identified by amino acid sequencing as glucose-regulated protein 78 (GRP78) and protein disulphide isomerase (PDI) [18].

Analytical, diagnostic and therapeutic context of Pdia3

  • Western blotting analysis showed that colon26 cells secrete a significant amount of ERp61 into culture medium, although most remains intracellular [11].
  • Nuclear ERp57 could also be detected by immunofluorescence in HeLa cells, where it showed an intracellular distribution clearly different from that of an homologous protein, located exclusively in the endoplasmic reticulum [19].
  • Sequence analysis showed that ERp57/GRP58 has two Trp-Cys-Gly-His-Cys-Lys motifs completely conserved among the mammals [16].
  • The gene array results were verified by quantitative real-time PCR that showed highly elevated transcript levels of genes involved in unfolded protein response such as ER and cytoplasmic chaperones, oxidoreductases, protein disulfide isomerase (PDI) family, and ER-associated degradation system such as ubiquitin [20].
  • Cell lysates of stable transfectomas contained 2-4-fold higher levels of PDI mRNA and increased levels of PDI protein, detected by immunoblotting, following induction with 0.1 microM dexamethasone [21].


  1. Downregulation of protein disulfide isomerase inhibits infection by the mouse polyomavirus. Gilbert, J., Ou, W., Silver, J., Benjamin, T. J. Virol. (2006) [Pubmed]
  2. Elevated expression of PDI family proteins during differentiation of mouse F9 teratocarcinoma cells. Miyaishi, O., Kozaki, K., Iida, K., Isobe, K., Hashizume, Y., Saga, S. J. Cell. Biochem. (1998) [Pubmed]
  3. Structure and assembly of the endoplasmic reticulum: biosynthesis and intracellular sorting of ERp61, ERp59, and ERp49, three protein components of murine endoplasmic reticulum. Lewis, M.J., Mazzarella, R.A., Green, M. Arch. Biochem. Biophys. (1986) [Pubmed]
  4. Enzymatic catalysis of disulfide formation. Noiva, R. Protein Expr. Purif. (1994) [Pubmed]
  5. Phosphatidylinositol-specific phospholipase C of Bacillus anthracis down-modulates the immune response. Zenewicz, L.A., Wei, Z., Goldfine, H., Shen, H. J. Immunol. (2005) [Pubmed]
  6. Impaired assembly of the major histocompatibility complex class I peptide-loading complex in mice deficient in the oxidoreductase ERp57. Garbi, N., Tanaka, S., Momburg, F., Hämmerling, G.J. Nat. Immunol. (2006) [Pubmed]
  7. ERp29 triggers a conformational change in polyomavirus to stimulate membrane binding. Magnuson, B., Rainey, E.K., Benjamin, T., Baryshev, M., Mkrtchian, S., Tsai, B. Mol. Cell (2005) [Pubmed]
  8. Genes regulating MHC class I processing of antigen. van Endert, P.M. Curr. Opin. Immunol. (1999) [Pubmed]
  9. Tissue distribution of three members of the murine protein disulfide isomerase (PDI) family. Marcus, N., Shaffer, D., Farrar, P., Green, M. Biochim. Biophys. Acta (1996) [Pubmed]
  10. Functions of ERp57 in the folding and assembly of major histocompatibility complex class I molecules. Zhang, Y., Baig, E., Williams, D.B. J. Biol. Chem. (2006) [Pubmed]
  11. Tissue distribution of ERp61 and association of its increased expression with IgG production in hybridoma cells. Kozaki, K., Miyaishi, O., Asai, N., Iida, K., Sakata, K., Hayashi, M., Nishida, T., Matsuyama, M., Shimizu, S., Kaneda, T. Exp. Cell Res. (1994) [Pubmed]
  12. A role for sperm surface protein disulfide isomerase activity in gamete fusion: evidence for the participation of ERp57. Ellerman, D.A., Myles, D.G., Primakoff, P. Dev. Cell (2006) [Pubmed]
  13. Identification by mutational analysis of amino acid residues essential in the chaperone function of calreticulin. Martin, V., Groenendyk, J., Steiner, S.S., Guo, L., Dabrowska, M., Parker, J.M., Müller-Esterl, W., Opas, M., Michalak, M. J. Biol. Chem. (2006) [Pubmed]
  14. KDEL proteins are found on the surface of NG108-15 cells. Xiao, G., Chung, T.F., Pyun, H.Y., Fine, R.E., Johnson, R.J. Brain Res. Mol. Brain Res. (1999) [Pubmed]
  15. Separate roles and different routing of calnexin and ERp57 in endoplasmic reticulum quality control revealed by interactions with asialoglycoprotein receptor chains. Frenkel, Z., Shenkman, M., Kondratyev, M., Lederkremer, G.Z. Mol. Biol. Cell (2004) [Pubmed]
  16. Molecular cloning of the human glucose-regulated protein ERp57/GRP58, a thiol-dependent reductase. Identification of its secretory form and inducible expression by the oncogenic transformation. Hirano, N., Shibasaki, F., Sakai, R., Tanaka, T., Nishida, J., Yazaki, Y., Takenawa, T., Hirai, H. Eur. J. Biochem. (1995) [Pubmed]
  17. Sensitivity of receptors for IgA on T560, a murine B lymphoma, to phorbol myristate acetate and to phosphatidylinositol-specific phospholipase C. Phillips-Quagliata, J.M., Rao, T.D., Maghazachi, A.A., González, A., Faria, A.M. Immunol. Res. (1991) [Pubmed]
  18. Lactation-associated and prolactin-responsive changes in protein synthesis in mouse mammary cells. Beaton, A., Wilkins, R.J., Wheeler, T.T. Tissue & cell. (1997) [Pubmed]
  19. Nuclear localization and DNA interaction of protein disulfide isomerase ERp57 in mammalian cells. Coppari, S., Altieri, F., Ferraro, A., Chichiarelli, S., Eufemi, M., Turano, C. J. Cell. Biochem. (2002) [Pubmed]
  20. Activation of endoplasmic reticulum stress response during the development of ischemic heart disease. Azfer, A., Niu, J., Rogers, L.M., Adamski, F.M., Kolattukudy, P.E. Am. J. Physiol. Heart Circ. Physiol. (2006) [Pubmed]
  21. Alteration of hybridoma viability and antibody secretion in transfectomas with inducible overexpression of protein disulfide isomerase. Kitchin, K., Flickinger, M.C. Biotechnol. Prog. (1995) [Pubmed]
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