# PDIA3

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Protein-coding gene in the species Homo sapiens

PDIA3 Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2ALB, 2DMM, 2H8L, 3F8U Identifiers Aliases PDIA3, 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 IDs OMIM: 602046; MGI: 95834; HomoloGene: 68454; GeneCards: PDIA3; OMA:PDIA3 - orthologs Gene location (Human) Chr. Chromosome 15 (human)[1] Band 15q15.3 Start 43,746,394 bp[1] End 43,773,279 bp[1] Gene location (Mouse) Chr. Chromosome 2 (mouse)[2] Band 2 E5|2 60.38 cM Start 121,244,256 bp[2] End 121,269,168 bp[2] RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in corpus epididymis stromal cell of endometrium caput epididymis beta cell left lobe of thyroid gland right lobe of thyroid gland anterior pituitary smooth muscle tissue mucosa of sigmoid colon rectum Top expressed in seminal vesicula decidua molar dermis mandibular prominence calvaria maxillary prominence stroma of bone marrow abdominal wall migratory enteric neural crest cell More reference expression data BioGPS n/a Gene ontology Molecular function disulfide oxidoreductase activity isomerase activity protein binding phospholipase C activity cysteine-type endopeptidase activity RNA binding protein disulfide isomerase activity identical protein binding Cellular component endoplasmic reticulum lumen focal adhesion melanosome myelin sheath cell surface endoplasmic reticulum extracellular exosome nucleus phagocytic vesicle recycling endosome membrane extracellular space MHC class I peptide loading complex Biological process protein import into nucleus antigen processing and presentation of peptide antigen via MHC class I protein folding in endoplasmic reticulum cell redox homeostasis response to endoplasmic reticulum stress protein retention in ER lumen protein folding positive regulation of extrinsic apoptotic signaling pathway signal transduction proteolysis antigen processing and presentation of exogenous peptide antigen via MHC class I, TAP-dependent cellular response to interleukin-7 Sources:Amigo / QuickGO Orthologs Species Human Mouse Entrez 2923 14827 Ensembl ENSG00000167004 ENSMUSG00000027248 UniProt P30101 P27773 RefSeq (mRNA) NM_005313 NM_007952 RefSeq (protein) NP_005304 NP_031978 Location (UCSC) Chr 15: 43.75 – 43.77 Mb Chr 2: 121.24 – 121.27 Mb PubMed search [3] [4] Wikidata View/Edit Human View/Edit Mouse

**Protein disulfide-isomerase A3** (**PDIA3**), also known as **glucose-regulated protein, 58-kD** (**GRP58**), is an [isomerase](/source/Isomerase) [enzyme](/source/Enzyme) encoded by the autosomal gene *PDIA3* in humans.[5][6][7][8] This protein [localizes](/source/Subcellular_localization) to the [endoplasmic reticulum](/source/Endoplasmic_reticulum) (ER) and interacts with [lectin](/source/Lectin) [chaperones](/source/Chaperone_(protein)) [calreticulin](/source/Calreticulin) and [calnexin](/source/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.[9]

## Structure

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](/source/Active_site) motifs (C57-G58-H59-C60 and C406-G407-H408-C409) and are catalytically active.[10][11] 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.[11] A transient [disulfide bond](/source/Disulfide_bond) forms between the [N-terminal](/source/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](/source/C-terminal) cysteine attacks the N-terminal cysteine to release the substrate.[10]

## Function

The PDIA3 protein is a [thiol](/source/Thiol) [oxidoreductase](/source/Oxidoreductase) that has [protein disulfide isomerase](/source/Protein_disulfide_isomerase) activity.[8][10] PDIA3 is also part of the [major histocompatibility complex](/source/Major_histocompatibility_complex) (MHC) class I [peptide loading complex](/source/Peptide_loading_complex), which is essential for formation of the final antigen conformation and export from the [endoplasmic reticulum](/source/Endoplasmic_reticulum) to the cell surface.[10][12] 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.[9][10] This function allows it to serve as a redox sensor by activating [mTORC1](/source/MTORC1), which then mediates mTOR complex assembly to adapt cells to oxidative damage. Thus, PDIA3 regulates [cell growth](/source/Cell_growth) and [death](/source/Apoptosis) according to oxygen concentrations, such as in the [hypoxic](/source/Hypoxia_(medical)) microenvironment of bones. Additionally, PDIA3 activates cell anchorage in bones by associating with [cell division](/source/Cell_division) and [cytoskeleton](/source/Cytoskeleton) proteins, such as beta-[actin](/source/Actin) and [vimentin](/source/Vimentin), to form a complex which controls [TUBB3](/source/TUBB3) folding and proper attachment of the [microtubules](/source/Microtubule) to the [kinetochore](/source/Kinetochore). PDIA3 also plays a role in [cytokine](/source/Cytokine)-dependent [signal transduction](/source/Signal_transduction), including [STAT3](/source/STAT3) signaling.[13]

PDIA3 may also participate in [Vitamin D](/source/Vitamin_D) (specifically, [calcitriol](/source/Calcitriol)) signaling as a membrane-bound receptor.[14]

## Clinical significance

It has been demonstrated that the downregulation of ERp57 expression is correlated with poor prognosis in early-stage cervical [cancer](/source/Cancer).[15] It has also been demonstrated that ERp57/PDIA3 binds specific DNA fragments in a melanoma cell line.[16] PDIA3 is also involved in bone [metastasis](/source/Metastasis), which is the most common source of distant relapse in [breast cancer](/source/Breast_cancer).[13] In addition to cancer, overexpression of PDIA3 is linked to [renal fibrosis](https://en.wikipedia.org/w/index.php?title=Renal_fibrosis&action=edit&redlink=1), which is characterized by excess synthesis and secretion of [ECM](/source/Extracellular_matrix) leading to ER stress.[17]

## Interactions

It has been demonstrated that PDIA3 interacts with:

- [BACE1](/source/BACE1),[18]

- [ERp27](/source/ERp27),[19]

- [tapasin](/source/Tapasin),[18][11]

- [CRT](/source/Calreticulin),[18] and

- [CNX](/source/CANX).[10][18][11]

## See also

- [Antigen processing](/source/Antigen_processing)

- [Major histocompatibility complex](/source/Major_histocompatibility_complex)

## References

1. ^ [***a***](#cite_ref-refGRCh38Ensembl_1-0) [***b***](#cite_ref-refGRCh38Ensembl_1-1) [***c***](#cite_ref-refGRCh38Ensembl_1-2) [GRCh38: Ensembl release 89: ENSG00000167004](http://May2017.archive.ensembl.org/Homo_sapiens/Gene/Summary?db=core;g=ENSG00000167004) – [Ensembl](/source/Ensembl_genome_database_project), May 2017

1. ^ [***a***](#cite_ref-refGRCm38Ensembl_2-0) [***b***](#cite_ref-refGRCm38Ensembl_2-1) [***c***](#cite_ref-refGRCm38Ensembl_2-2) [GRCm38: Ensembl release 89: ENSMUSG00000027248](http://May2017.archive.ensembl.org/Mus_musculus/Gene/Summary?db=core;g=ENSMUSG00000027248) – [Ensembl](/source/Ensembl_genome_database_project), May 2017

1. **[^](#cite_ref-3)** ["Human PubMed Reference:"](https://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Link&LinkName=gene_pubmed&from_uid=2923). *National Center for Biotechnology Information, U.S. National Library of Medicine*.

1. **[^](#cite_ref-4)** ["Mouse PubMed Reference:"](https://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Link&LinkName=gene_pubmed&from_uid=14827). *National Center for Biotechnology Information, U.S. National Library of Medicine*.

1. **[^](#cite_ref-5)** ["Symbol report for PDIA3"](https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/4606). *HGNC*. HUGO Gene Nomenclature Committee. Retrieved 7 February 2024.

1. **[^](#cite_ref-pmid7487104_6-0)** 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"](https://doi.org/10.1006%2Fabbi.1995.0060). *Archives of Biochemistry and Biophysics*. **323** (2): 397–403. [doi](/source/Doi_(identifier)):[10.1006/abbi.1995.0060](https://doi.org/10.1006%2Fabbi.1995.0060). [PMID](/source/PMID_(identifier)) [7487104](https://pubmed.ncbi.nlm.nih.gov/7487104).

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1. ^ [***a***](#cite_ref-entrez_9-0) [***b***](#cite_ref-entrez_9-1) ["Entrez Gene: PDIA3 protein disulfide isomerase family A, member 3"](https://www.ncbi.nlm.nih.gov/gene/2923).

1. ^ [***a***](#cite_ref-pmid19119025_10-0) [***b***](#cite_ref-pmid19119025_10-1) [***c***](#cite_ref-pmid19119025_10-2) [***d***](#cite_ref-pmid19119025_10-3) [***e***](#cite_ref-pmid19119025_10-4) [***f***](#cite_ref-pmid19119025_10-5) 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"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2650231). *Immunity*. **30** (1): 21–32. [doi](/source/Doi_(identifier)):[10.1016/j.immuni.2008.10.018](https://doi.org/10.1016%2Fj.immuni.2008.10.018). [PMC](/source/PMC_(identifier)) [2650231](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2650231). [PMID](/source/PMID_(identifier)) [19119025](https://pubmed.ncbi.nlm.nih.gov/19119025).

1. ^ [***a***](#cite_ref-pmid16905107_11-0) [***b***](#cite_ref-pmid16905107_11-1) [***c***](#cite_ref-pmid16905107_11-2) [***d***](#cite_ref-pmid16905107_11-3) 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"](https://doi.org/10.1016%2Fj.str.2006.06.019). *Structure*. **14** (8): 1331–9. [doi](/source/Doi_(identifier)):[10.1016/j.str.2006.06.019](https://doi.org/10.1016%2Fj.str.2006.06.019). [PMID](/source/PMID_(identifier)) [16905107](https://pubmed.ncbi.nlm.nih.gov/16905107).

1. **[^](#cite_ref-pmid16311600_12-0)** 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](/source/Doi_(identifier)):[10.1038/ni1288](https://doi.org/10.1038%2Fni1288). [PMID](/source/PMID_(identifier)) [16311600](https://pubmed.ncbi.nlm.nih.gov/16311600). [S2CID](/source/S2CID_(identifier)) [5857455](https://api.semanticscholar.org/CorpusID:5857455).

1. ^ [***a***](#cite_ref-pmid23625662_13-0) [***b***](#cite_ref-pmid23625662_13-1) 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"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3734573). *Molecular & Cellular Proteomics*. **12** (8): 2111–25. [doi](/source/Doi_(identifier)):[10.1074/mcp.M112.022772](https://doi.org/10.1074%2Fmcp.M112.022772). [PMC](/source/PMC_(identifier)) [3734573](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3734573). [PMID](/source/PMID_(identifier)) [23625662](https://pubmed.ncbi.nlm.nih.gov/23625662).

1. **[^](#cite_ref-pmid27897272_14-0)** Gaucci E, Raimondo D, Grillo C, Cervoni L, Altieri F, Nittari G, et al. (November 2016). ["Analysis of the interaction of calcitriol with the disulfide isomerase ERp57"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5126700). *Scientific Reports*. **6** 37957. [Bibcode](/source/Bibcode_(identifier)):[2016NatSR...637957G](https://ui.adsabs.harvard.edu/abs/2016NatSR...637957G). [doi](/source/Doi_(identifier)):[10.1038/srep37957](https://doi.org/10.1038%2Fsrep37957). [PMC](/source/PMC_(identifier)) [5126700](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5126700). [PMID](/source/PMID_(identifier)) [27897272](https://pubmed.ncbi.nlm.nih.gov/27897272).

1. **[^](#cite_ref-15)** 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"](https://zenodo.org/record/897050). *Biomarkers*. **18** (7): 573–9. [doi](/source/Doi_(identifier)):[10.3109/1354750X.2013.827742](https://doi.org/10.3109%2F1354750X.2013.827742). [PMID](/source/PMID_(identifier)) [23957851](https://pubmed.ncbi.nlm.nih.gov/23957851). [S2CID](/source/S2CID_(identifier)) [23970844](https://api.semanticscholar.org/CorpusID:23970844).

1. **[^](#cite_ref-16)** 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](/source/Doi_(identifier)):[10.1016/j.gene.2013.04.004](https://doi.org/10.1016%2Fj.gene.2013.04.004). [hdl](/source/Hdl_(identifier)):[11573/516861](https://hdl.handle.net/11573%2F516861). [PMID](/source/PMID_(identifier)) [23587917](https://pubmed.ncbi.nlm.nih.gov/23587917).

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1. ^ [***a***](#cite_ref-pmid12052826_18-0) [***b***](#cite_ref-pmid12052826_18-1) [***c***](#cite_ref-pmid12052826_18-2) [***d***](#cite_ref-pmid12052826_18-3) 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"](https://doi.org/10.1074%2Fjbc.M202405200). *The Journal of Biological Chemistry*. **277** (33): 29686–97. [doi](/source/Doi_(identifier)):[10.1074/jbc.M202405200](https://doi.org/10.1074%2Fjbc.M202405200). [PMID](/source/PMID_(identifier)) [12052826](https://pubmed.ncbi.nlm.nih.gov/12052826).

1. **[^](#cite_ref-19)** 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"](https://doi.org/10.1074%2Fjbc.M604314200). *The Journal of Biological Chemistry*. **281** (44): 33727–38. [doi](/source/Doi_(identifier)):[10.1074/jbc.M604314200](https://doi.org/10.1074%2Fjbc.M604314200). [PMID](/source/PMID_(identifier)) [16940051](https://pubmed.ncbi.nlm.nih.gov/16940051).

## External links

- [PDIA3+protein,+human](https://meshb.nlm.nih.gov/record/ui?name=PDIA3+protein%2C+human) at the U.S. National Library of Medicine [Medical Subject Headings](/source/Medical_Subject_Headings) (MeSH)

v t e Isomerases: intramolecular oxidoreductases (EC 5.3) 5.3.1: Aldoses/Ketoses Triosephosphate isomerase Ribose-5-phosphate isomerase Mannose phosphate isomerase Glucose isomerase 5.3.2: Keto/Enol Phenylpyruvate tautomerase Oxaloacetate tautomerase 4-Oxalocrotonate tautomerase 5.3.3: C = C Steroid D-isomerase Isopentenyl-diphosphate delta isomerase Vinylacetyl-CoA D-isomerase Muconolactone D-isomerase Cholestenol Delta-isomerase (EBP) Methylitaconate D-isomerase Aconitate Delta-isomerase Enoyl CoA isomerase Prostaglandin-A1 Delta-isomerase 5-carboxymethyl-2-hydroxymuconate D-isomerase Isopiperitenone D-isomerase L-dopachrome isomerase Polyenoic fatty acid isomerase 5.3.4: S-S Protein disulfide-isomerase (PDIA3) 5.3.99: other Prostaglandin D2 synthase/Prostaglandin-D synthase Prostaglandin E synthase Prostacyclin synthase Thromboxane-A synthase

v t e Enzymes Activity Active site Binding site Catalytic triad Oxyanion hole Enzyme promiscuity Diffusion-limited enzyme Cofactor Enzyme catalysis Regulation Allosteric regulation Cooperativity Enzyme inhibitor Enzyme activator Classification EC number Enzyme superfamily Enzyme family List of enzymes Kinetics Enzyme kinetics Eadie–Hofstee diagram Hanes–Woolf plot Lineweaver–Burk plot Michaelis–Menten kinetics Types EC1 Oxidoreductases (list) EC2 Transferases (list) EC3 Hydrolases (list) EC4 Lyases (list) EC5 Isomerases (list) EC6 Ligases (list) EC7 Translocases (list)

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Adapted from the Wikipedia article [PDIA3](https://en.wikipedia.org/wiki/PDIA3) by Wikipedia contributors ([contributor history](https://en.wikipedia.org/wiki/PDIA3?action=history)). Available under [Creative Commons Attribution-ShareAlike 4.0 International](https://creativecommons.org/licenses/by-sa/4.0/). Changes may have been made.