The reference OMIM entry for this protein is 602046
Protein disulfide isomerase, family a, member 3; pdia3
Glucose-regulated protein, 58-kd; grp58
Erp57
Er60
CLONING
The cDNA encoding human GRP58 was cloned independently by Bourdi et al. (1995), Koivunen et al. (1996), and Hirano et al. (1995). All reported that the gene encodes a 505-amino acid polypeptide with significant homology to human protein disulfide isomerase (PDI;
176790). Bourdi et al. (1995) noted that the sequence includes a putative nuclear localization motif and an endoplasmic reticulum (ER)-retention/retrieval motif. Koivunen et al. (1997) noted that the GRP58 sequence has 2 thioredoxin-like domains. Koivunen et al. (1997) showed by Northern blotting that GRP58 is expressed as a 2-kb message most abundantly in liver, placenta, and lung, and at lower levels in all other tissues tested.
GENE FUNCTION
Several laboratories have examined the functional properties of GRP58. Bourdi et al. (1995) found that the GRP58 protein had protein disulfide isomerase activity. Koivunen et al. (1996) showed that GRP58 could not substitute for the beta subunit of PDI. When coexpressed with alpha prolyl 4-hydroxylase, GRP58 did not form prolyl 4-hydroxylase tetramers, nor did it have prolyl 4-hydroxylase activity. Hirano et al. (1995) expressed human GRP58 and found that the protein had a thiol-dependent reductase activity. They showed that the expression level of GRP58 is increased after oncogenic transformation of normal rat kidney cells and NIH 3T3 cells. Oliver et al. (1997) used a crosslinking approach to screen antisera to several ER luminal proteins in order to find proteins that interact specifically with glycoproteins in the ER. They identified GRP58 as one such protein. The authors suggested that GRP58 functions in combination with calnexin (
114217) and calreticulin (
109091) as a molecular chaperone of glycoprotein biosynthesis. Using specific antibodies and inhibitors of PDI activity, Ellerman et al. (2006) determined that Erp57 on the surface of the mouse sperm head was involved in sperm-egg fusion. They hypothesized that thiol-disulfide exchange in gamete fusion may produce conformational changes in fusion-active proteins.
GENE STRUCTURE
Koivunen et al. (1997) examined the genomic organization of the GRP58 gene and reported that it is encoded on 13 exons spanning 18 kb; no similarity was found between the genomic structures of the GRP58, PDI, and thioredoxin (
187700) genes.
MAPPING
Koivunen et al. (1997) used fluorescence in situ hybridization to map the GRP58 gene to human chromosome 15q15. They also observed that humans have a processed pseudogene, GRP58P, which is nearly identical to GRP58 and maps to chromosome 1q21. By Southern blot analysis of an interspecific backcross, Briquet-Laugier et al. (1998) mapped the Grp58 gene to mouse chromosome 2.
ANIMAL MODEL
PDIA3 is part of the major histocompatibility complex (MHC) class I peptide-loading complex (see TAP1;
170260), which is essential for final antigen conformation and export from the ER to the cell surface. To avoid embryonic lethality, Garbi et al. (2006) generated mice with a conditional deletion of Pdia3 in the B-cell compartment. These mice retained functional B cells with decreased MHC class I expression, as shown by flow cytometry and immunoblot analysis. Immunoprecipitation analysis showed that Pdia3 mediated recruitment of MHC class I molecules and Calr (
109091) into the peptide-loading complex. Lack of Pdia3 resulted in suboptimal peptide loading and decreased T-cell activation. Garbi et al. (2006) concluded that ...
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Feb. 2, 2018: Protein entry updated
Automatic update: Uniprot description updated
Dec. 19, 2017: Protein entry updated
Automatic update: Uniprot description updated
March 16, 2016: Protein entry updated
Automatic update: OMIM entry 602046 was added.