| Protein Disulfide Isomerase Family A Member 3 | |
|---|---|
| Gene Symbol | PDIA3 |
| Full Name | Protein Disulfide Isomerase Family A Member 3 |
| Chromosome | 15q15.3 |
| NCBI Gene ID | 10195 |
| OMIM | 604046 |
| Ensembl ID | ENSG00000167077 |
| UniProt ID | P27773 |
| Associated Diseases | Alzheimer's Disease, Parkinson's Disease, Cancer |
PDIA3 (Protein Disulfide Isomerase Family A Member 3), also known as ERP57 (Endoplasmic Reticulum Protein 57) or GRP58, is a multifunctional ER-resident protein that plays critical roles in protein folding, redox homeostasis, and cellular stress responses. As a member of the protein disulfide isomerase family, PDIA3 catalyzes the formation, reduction, and rearrangement of disulfide bonds in nascent polypeptides, ensuring proper protein tertiary and quaternary structure.[1] Beyond its canonical enzymatic function, PDIA3 serves as a molecular chaperone, facilitates ER-associated degradation (ERAD), and participates in calcium homeostasis.[2] Recent research has implicated PDIA3 in the pathogenesis of neurodegenerative diseases, particularly Alzheimer's disease (AD) and Parkinson's disease (PD), where it helps manage protein folding stress and interacts with disease-relevant proteins including amyloid precursor protein (APP) and alpha-synuclein.[3]
PDIA3 catalyzes the formation and rearrangement of disulfide bonds in nascent proteins, which is essential for proper protein folding in the ER. PDIA3 has a redox-active thioredoxin domain and can act as both an oxidase and reductase. It forms complexes with other ER chaperones including calnexin (CALR) and calreticulin (CALR). PDIA3 also plays roles in ER-associated degradation (ERAD) and calcium homeostasis. It can translocate to the cell surface where it has distinct functions in cell adhesion and signaling.
PDIA3 is involved in neurodegenerative diseases through its chaperone and disulfide bond formation activities. In Alzheimer's disease, PDIA3 interacts with amyloid precursor protein (APP) and may influence amyloid-beta production. It is upregulated in AD brain and responds to ER stress. In Parkinson's disease, PDIA3 may help manage protein folding stress in dopaminergic neurons. PDIA3 has been shown to interact with alpha-synuclein and may be involved in its aggregation. Genetic variants in PDIA3 have been associated with increased risk for neurodegenerative diseases.
PDIA3 is widely expressed in all tissues, with high expression in brain, liver, and pancreas. In the brain, it is expressed in neurons and glial cells across various regions including hippocampus, cortex, and basal ganglia. Expression is upregulated by ER stress and during the unfolded protein response.