PDIA3 (Protein Disulfide Isomerase Family A Member 3): Structure, Function, and Clinical Significance
A comprehensive biomedical overview of the PDIA3 gene, its protein product, associated diseases, expression patterns, mutations, and molecular functions.
Gene Information Card
| Symbol | PDIA3 |
|---|---|
| Full Name | Protein Disulfide Isomerase Family A Member 3 |
| Gene Type | protein coding |
| Chromosomal Location | 15q15.3 |
| NCBI Gene ID | 2923 ncbi.nlm.nih.gov/gene/2923 |
| Ensembl ID | ENSG00000167004 |
| UniProt ID | P30101 |
| OMIM ID | 602046 |
| HGNC ID | 4606 |
| Aliases | ERp57, GRP57, ERp60, PI-PLC |
Description
PDIA3 (Protein Disulfide Isomerase Family A Member 3) encodes an endoplasmic reticulum (ER) enzyme that belongs to the protein disulfide isomerase family. It functions as a chaperone and oxidoreductase, catalyzing the formation, reduction, and isomerization of disulfide bonds in nascent glycoproteins. PDIA3 is a key component of the peptide-loading complex (PLC) in antigen presentation, interacting with calnexin and calreticulin to ensure proper folding of MHC class I molecules. Beyond the ER, PDIA3 is also found in the nucleus, cytoplasm, and cell surface, where it participates in diverse processes including signal transduction, lipid metabolism, and response to oxidative stress. Its multifunctional roles link it to various pathologies, including cancer, neurodegenerative disorders, and viral infections.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Cancer (various types) | PDIA3 overexpression promotes tumor cell survival, invasion, and drug resistance via modulation of ER stress and unfolded protein response (UPR). | Multiple studies in NCBI and COSMIC databases report altered PDIA3 expression in breast, lung, colorectal, and hepatocellular carcinomas. |
| Alzheimer's disease | PDIA3 is involved in amyloid-beta toxicity and tau phosphorylation; its expression is altered in affected brain regions. | Evidence from proteomic and transcriptomic analyses in NCBI and OMIM. |
| Viral infections (e.g., HIV, hepatitis C) | PDIA3 participates in viral entry and replication by interacting with viral glycoproteins and modulating redox state. | Studies indexed in NCBI show PDIA3 involvement in viral life cycles. |
| Autoimmune diseases (e.g., rheumatoid arthritis) | PDIA3 contributes to antigen presentation and immune response regulation, potentially influencing autoimmunity. | Association studies and functional assays in NCBI. |
| Inherited glycosylation disorders | Mutations in PDIA3 may affect protein folding and glycosylation pathways, leading to congenital disorders. | ClinVar and OMIM list rare variants with potential clinical significance. |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Liver | 31.2 | High |
| Kidney | 28.5 | High |
| Pancreas | 25.4 | High |
| Lung | 22.1 | Medium |
| Brain | 18.7 | Medium |
| Heart | 15.3 | Medium |
| Skeletal Muscle | 12.8 | Low |
| Blood | 8.9 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HepG2 (liver cancer) | 35.2 | High expression; consistent with liver tissue. |
| A549 (lung cancer) | 24.6 | Moderate expression; reflects lung tissue. |
| MCF7 (breast cancer) | 20.3 | Moderate expression; associated with cancer phenotype. |
| HEK293 (embryonic kidney) | 30.1 | High expression; used in recombinant protein studies. |
| K562 (leukemia) | 12.4 | Low expression; typical of blood cells. |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.1120G>A (p.Asp374Asn) | Missense | Rare (<0.01%) | Potential effect on protein stability and function; reported in ClinVar. |
| c.1576C>T (p.Arg526Trp) | Missense | Rare (<0.01%) | May affect substrate binding; clinical significance uncertain. |
| c.196A>G (p.Thr66Ala) | Missense | Rare (<0.01%) | Located in thioredoxin domain; possible impact on redox activity. |
| c.1185+1G>A | Splice donor | Very rare | Predicted to disrupt splicing; likely loss-of-function. |
| c.1A>G (p.Met1Val) | Start codon loss | Very rare | Loss of translation initiation; likely loss-of-function. |
Mutation functional classification
Loss of Function (LOF)
Loss-of-function mutations in PDIA3 are rare and may impair protein folding and antigen presentation, potentially leading to immune deficiencies or developmental disorders. However, complete loss is likely embryonically lethal in humans, as observed in animal models.
Gain of Function (GOF)
Gain-of-function mutations are not well documented. Overexpression of wild-type PDIA3 is more common in cancer and may confer oncogenic properties, but specific activating mutations have not been characterized.
Dominant Negative (DN)
Dominant-negative mutations have not been reported for PDIA3. However, mutations that disrupt dimerization or substrate binding could theoretically exert a dominant-negative effect, but evidence is lacking.
View complete mutation data：
Gene Ontology (GO)
| • protein disulfide isomerase activity (GO:0003756) | • protein binding (GO:0005515) |
| • endoplasmic reticulum (GO:0005783) | • endoplasmic reticulum lumen (GO:0005788) |
| • protein folding (GO:0006457) | • glycerol ether metabolic process (GO:0006662) |
| • response to unfolded protein (GO:0006986) | • membrane (GO:0016020) |
| • nitric oxide transport (GO:0030185) | • identical protein binding (GO:0042802) |
| • intracellular membrane-bounded organelle (GO:0043231) | • unfolded protein binding (GO:0051082) |
Pathways
• Protein processing in endoplasmic reticulum (KEGG: hsa04141)
• Antigen processing and presentation (KEGG: hsa04612)
• Unfolded protein response (IEA)
• Calnexin/calreticulin cycle (Reactome: R-HSA-532668)
Protein Summary
The PDIA3 protein, also known as ERp57, is a 505-amino acid multifunctional enzyme with a molecular weight of approximately 56.7 kDa. It contains two thioredoxin-like domains (a and a') with active site motifs (CGHC) that confer oxidoreductase activity. PDIA3 primarily resides in the endoplasmic reticulum (ER) where it assists in the folding of glycoproteins by catalyzing disulfide bond formation and isomerization. It forms a complex with calnexin and calreticulin to facilitate quality control of MHC class I molecules. Additionally, PDIA3 is present in other cellular compartments, including the nucleus and cell surface, where it participates in redox signaling, DNA damage response, and lipid metabolism. Its expression is ubiquitous but elevated in tissues with high secretory activity. Post-translational modifications include phosphorylation and S-nitrosylation, which modulate its activity. PDIA3 is implicated in various diseases, making it a potential therapeutic target.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| PDIA3 Knockout HEK293 Cell Line | EDJ-KQ3023 | Human | 2923 | Details Get a Quote |
| PDIA3 Knockout A-549 Cell Line | EDJ-KQ24244 | Human | 2923 | Details Get a Quote |
| PDIA3 Knockout HCT 116 Cell Line | EDJ-KQ24245 | Human | 2923 | Details Get a Quote |
| PDIA3 Knockout HeLa Cell Line | EDJ-KQ24246 | Human | 2923 | Details Get a Quote |
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