Protein disulfide-isomerase A3 (PDIA3), also known as glucose-regulated protein, 58-kD (GRP58), is an isomeraseenzyme. This protein localizes to the endoplasmic reticulum (ER) and interacts with lectinchaperonescalreticulin 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.
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. 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. 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.
It has been demonstrated that the downregulation of ERp57 expression is correlated with poor prognosis in early-stage cervical cancer. It has also been demonstrated that ERp57/PDIA3 binds specific DNA fragments in a melanoma cell line. PDIA3 is also involved in bone metastasis, which is the most common source of distant relapse in breast cancer. 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.
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