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Available structures
PDBOrtholog search: PDBe RCSB
AliasesPDIA3, protein disulfide isomerase family A, member 3, ER60, ERp57, ERp60, ERp61, GRP57, GRP58, HEL-S-269, HEL-S-93n, HsT17083, P58, PI-PLC, protein disulfide isomerase family A member 3
External IDsMGI: 95834 HomoloGene: 68454 GeneCards: PDIA3
Gene location (Human)
Chromosome 15 (human)
Chr.Chromosome 15 (human)[1]
Chromosome 15 (human)
Genomic location for PDIA3
Genomic location for PDIA3
Band15q15.3Start43,746,410 bp[1]
End43,773,278 bp[1]
RefSeq (mRNA)



RefSeq (protein)



Location (UCSC)Chr 15: 43.75 – 43.77 MbChr 2: 121.41 – 121.44 Mb
PubMed search[3][4]
View/Edit HumanView/Edit Mouse

Protein disulfide-isomerase A3 (PDIA3), also known as glucose-regulated protein, 58-kD (GRP58), is an isomerase enzyme.[5][6][7] This protein localizes to the endoplasmic reticulum (ER) and interacts with lectin chaperones calreticulin and calnexin (CNX) to modulate folding of newly synthesized glycoproteins. It is thought that complexes of lectins and this protein mediate protein folding by promoting formation of disulfide bonds in their glycoprotein substrates.[8]


The PDIA3 protein consists of four thioredoxin-like domains: a, b, b′, and a′. The a and a′ domains have Cys-Gly-His-Cys active site motifs (C57-G58-H59-C60 and C406-G407-H408-C409) and are catalytically active.[9][10] The bb′ domains contain a CNX binding site, which is composed of positively charged, highly conserved residues (K214, K274, and R282) that interact with the negatively charged residues of the CNX P domain. The b′ domain comprises the majority of the binding site, but the β4-β5 loop of the b domain provides additional contact (K214) to strengthen the interaction.[10] A transient disulfide bond forms between the N-terminal cysteine in the catalytic motif and a substrate, but in a step called "escape pathway", the bond is disrupted as the C-terminal cysteine attacks the N-terminal cysteine to release the substrate.[9]


The PDIA3 protein is a thiol oxidoreductase that has protein disulfide isomerase activity.[7][9] PDIA3 is also part of the major histocompatibility complex (MHC) class I peptide loading complex, which is essential for formation of the final antigen conformation and export from the endoplasmic reticulum to the cell surface.[9][11] This protein of the endoplasmic reticulum interacts with lectin chaperones such as calreticulin and CNX in order to modulate the folding of proteins that are newly synthesized. It is believed that PDIA3 plays a role in protein folding by promoting the formation of disulfide bonds, and that CNX facilitates the positioning substrates next to the catalytic cysteines.[8][9] This function allows it to serve as a redox sensor by activating mTORC1, which then mediates mTOR complex assembly to adapt cells to oxidative damage. Thus, PDIA3 regulates cell growth and death according to oxygen concentrations, such as in the hypoxic microenvironment of bones. Additionally, PDIA3 activates cell anchorage in bones by associating with cell division and cytoskeleton proteins, such as beta-actin and vimentin, to form a complex which controls TUBB3 folding and proper attachment of the microtubules to the kinetochore. PDIA3 also plays a role in cytokine-dependent signal transduction, including STAT3 signaling.[12]

Clinical significance[edit]

It has been demonstrated that the downregulation of ERp57 expression is correlated with poor prognosis in early-stage cervical cancer.[13] It has also been demonstrated that ERp57/PDIA3 binds specific DNA fragments in a melanoma cell line.[14] PDIA3 is also involved in bone metastasis, which is the most common source of distant relapse in breast cancer.[12] In addition to cancer, overexpression of PDIA3 is linked to renal fibrosis, which is characterized by excess synthesis and secretion of ECM leading to ER stress.[15]


It has been demonstrated that PDIA3 interacts with:

See also[edit]


  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000167004 - Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000027248 - Ensembl, May 2017
  3. ^ "Human PubMed Reference:".
  4. ^ "Mouse PubMed Reference:".
  5. ^ Bourdi M, Demady D, Martin JL, Jabbour SK, Martin BM, George JW, Pohl LR (Nov 1995). "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". Archives of Biochemistry and Biophysics. 323 (2): 397–403. doi:10.1006/abbi.1995.0060. PMID 7487104.
  6. ^ Hirano N, Shibasaki F, Sakai R, Tanaka T, Nishida J, Yazaki Y, Takenawa T, Hirai H (Nov 1995). "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". European Journal of Biochemistry / FEBS. 234 (1): 336–42. doi:10.1111/j.1432-1033.1995.336_c.x. PMID 8529662.
  7. ^ a b Koivunen P, Helaakoski T, Annunen P, Veijola J, Räisänen S, Pihlajaniemi T, Kivirikko KI (Jun 1996). "ERp60 does not substitute for protein disulphide isomerase as the beta-subunit of prolyl 4-hydroxylase". The Biochemical Journal. 316. 316 (2): 599–605. doi:10.1042/bj3160599. PMC 1217390. PMID 8687406.
  8. ^ a b "Entrez Gene: PDIA3 protein disulfide isomerase family A, member 3".
  9. ^ a b c d e f Dong G, Wearsch PA, Peaper DR, Cresswell P, Reinisch KM (Jan 2009). "Insights into MHC class I peptide loading from the structure of the tapasin-ERp57 thiol oxidoreductase heterodimer". Immunity. 30 (1): 21–32. doi:10.1016/j.immuni.2008.10.018. PMC 2650231. PMID 19119025.
  10. ^ a b c d Kozlov G, Maattanen P, Schrag JD, Pollock S, Cygler M, Nagar B, Thomas DY, Gehring K (Aug 2006). "Crystal structure of the bb' domains of the protein disulfide isomerase ERp57". Structure. 14 (8): 1331–9. doi:10.1016/j.str.2006.06.019. PMID 16905107.
  11. ^ Garbi N, Tanaka S, Momburg F, Hämmerling GJ (Jan 2006). "Impaired assembly of the major histocompatibility complex class I peptide-loading complex in mice deficient in the oxidoreductase ERp57". Nature Immunology. 7 (1): 93–102. doi:10.1038/ni1288. PMID 16311600.
  12. ^ a b Santana-Codina N, Carretero R, Sanz-Pamplona R, Cabrera T, Guney E, Oliva B, Clezardin P, Olarte OE, Loza-Alvarez P, Méndez-Lucas A, Perales JC, Sierra A (Aug 2013). "A transcriptome-proteome integrated network identifies endoplasmic reticulum thiol oxidoreductase (ERp57) as a hub that mediates bone metastasis". Molecular & Cellular Proteomics. 12 (8): 2111–25. doi:10.1074/mcp.M112.022772. PMC 3734573. PMID 23625662.
  13. ^ Chung H, Cho H, Perry C, Song J, Ylaya K, Lee H, Kim JH (Nov 2013). "Downregulation of ERp57 expression is associated with poor prognosis in early-stage cervical cancer". Biomarkers. 18 (7): 573–9. doi:10.3109/1354750X.2013.827742. PMID 23957851.
  14. ^ Aureli C, Gaucci E, Arcangeli V, Grillo C, Eufemi M, Chichiarelli S (Jul 2013). "ERp57/PDIA3 binds specific DNA fragments in a melanoma cell line". Gene. 524 (2): 390–5. doi:10.1016/j.gene.2013.04.004. PMID 23587917.
  15. ^ Dihazi H, Dihazi GH, Bibi A, Eltoweissy M, Mueller CA, Asif AR, Rubel D, Vasko R, Mueller GA (Aug 2013). "Secretion of ERP57 is important for extracellular matrix accumulation and progression of renal fibrosis, and is an early sign of disease onset". Journal of Cell Science. 126 (Pt 16): 3649–63. doi:10.1242/jcs.125088. PMID 23781031.
  16. ^ a b c d Leach MR, Cohen-Doyle MF, Thomas DY, Williams DB (Aug 2002). "Localization of the lectin, ERp57 binding, and polypeptide binding sites of calnexin and calreticulin". The Journal of Biological Chemistry. 277 (33): 29686–97. doi:10.1074/jbc.M202405200. PMID 12052826.
  17. ^ Alanen HI, Williamson RA, Howard MJ, Hatahet FS, Salo KE, Kauppila A, Kellokumpu S, Ruddock LW (Nov 2006). "ERp27, a new non-catalytic endoplasmic reticulum-located human protein disulfide isomerase family member, interacts with ERp57". The Journal of Biological Chemistry. 281 (44): 33727–38. doi:10.1074/jbc.M604314200. PMID 16940051.

External links[edit]