Protein disulfide-isomerase A6 (PDIA6)
The protein contains 440 amino acids for an estimated molecular weight of 48121 Da.
May function as a chaperone that inhibits aggregation of misfolded proteins (PubMed:12204115). Negatively regulates the unfolded protein response (UPR) through binding to UPR sensors such as ERN1, which in turn inactivates ERN1 signaling (PubMed:24508390). May also regulate the UPR via the EIF2AK3 UPR sensor (PubMed:24508390). Plays a role in platelet aggregation and activation by agonists such as convulxin, collagen and thrombin (PubMed:15466936). (updated: Dec. 20, 2017)
Protein identification was indicated in the following studies:
- Goodman and co-workers. (2013) The proteomics and interactomics of human erythrocytes. Exp Biol Med (Maywood) 238(5), 509-518.
- Lange and co-workers. (2014) Annotating N termini for the human proteome project: N termini and Nα-acetylation status differentiate stable cleaved protein species from degradation remnants in the human erythrocyte proteome. J Proteome Res. 13(4), 2028-2044.
- Hegedűs and co-workers. (2015) Inconsistencies in the red blood cell membrane proteome analysis: generation of a database for research and diagnostic applications. Database (Oxford) 1-8.
- Wilson and co-workers. (2016) Comparison of the Proteome of Adult and Cord Erythroid Cells, and Changes in the Proteome Following Reticulocyte Maturation. Mol Cell Proteomics. 15(6), 1938-1946.
- Bryk and co-workers. (2017) Quantitative Analysis of Human Red Blood Cell Proteome. J Proteome Res. 16(8), 2752-2761.
- D'Alessandro and co-workers. (2017) Red blood cell proteomics update: is there more to discover? Blood Transfus. 15(2), 182-187.
- Chu and co-workers. (2018) Quantitative mass spectrometry of human reticulocytes reveal proteome-wide modifications during maturation. Br J Haematol. 180(1), 118-133.
Methods
The following articles were analysed to gather the proteome content of erythrocytes.
The gene or protein list provided in the studies were processed using the ID mapping API of Uniprot in September 2018. The number of proteins identified and mapped without ambiguity in these studies is indicated below.
Only Swiss-Prot entries (reviewed) were considered for protein evidence assignation.
| Publication | Identification 1 | Uniprot mapping 2 | Not mapped / Obsolete | TrEMBL | Swiss-Prot |
|---|---|---|---|---|---|
| Goodman (2013) | 2289 (gene list) | 2278 | 53 | 20599 | 2269 |
| Lange (2014) | 1234 | 1234 | 7 | 28 | 1224 |
| Hegedus (2015) | 2638 | 2622 | 0 | 235 | 2387 |
| Wilson (2016) | 1658 | 1528 | 170 | 291 | 1068 |
| d'Alessandro (2017) | 1826 | 1817 | 2 | 0 | 1815 |
| Bryk (2017) | 2090 | 2060 | 10 | 108 | 1942 |
| Chu (2018) | 1853 | 1804 | 55 | 362 | 1387 |
1 as available in the article and/or in supplementary material
2 uniprot mapping returns all protein isoforms as one entry
The compilation of older studies can be retrieved from the Red Blood Cell Collection database.
The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.
This protein is annotated as membranous in Gene Ontology, is annotated as membranous in UniProt.
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| Variant | Description |
|---|---|
| dbSNP:rs4807 |
Biological Process
Apoptotic cell clearance
Cell redox homeostasis
Cellular protein metabolic process
Endoplasmic reticulum unfolded protein response
IRE1-mediated unfolded protein response
Obsolete activation of signaling protein activity involved in unfolded protein response
Post-translational protein modification
Protein folding
Response to endoplasmic reticulum stress
The reference OMIM entry for this protein is 611099
Protein disulfide isomerase, family a, member 6; pdia6
P5
Endoplasmic reticulum protein 5; erp5
DESCRIPTION
Protein disulfide isomerases (EC 5.3.4.1), such as PDIA6, are endoplasmic reticulum (ER) resident proteins that catalyze formation, reduction, and isomerization of disulfide bonds in proteins and are thought to play a role in folding of disulfide-bonded proteins (Hayano and Kikuchi, 1995).CLONING
By screening a placenta cDNA library with a PDI (P4HB; 176790) cDNA fragment, Hayano and Kikuchi (1995) cloned PDIA6, which they called P5. The deduced 440-amino acid protein has a calculated molecular mass of 48.1 kD. It has a putative N-terminal signal sequence, followed by 2 thioredoxin (TXN; 187700)-like domains and a C-terminal ER retention signal (KDEL). Chaudhuri et al. (1992) found that mouse P5 showed highest expression in lung, with progressively lower levels in kidney, heart, liver, and brain.GENE FUNCTION
Chaudhuri et al. (1992) showed that P5, Rrm2 (180410), and Odc1 (154640) were coamplified in hamster cells resistant to hydroxyurea, a potent inhibitor of ribonucleotide reductase. Since P5, RRM2, and ODC1 are closely linked in the hamster and human genomes, Chaudhuri et al. (1992) hypothesized that they may form an amplicon. Kikuchi et al. (2002) found that recombinant human P5 had both isomerase and chaperone activities, but both activities were lower than those of human PDI. P5 showed peptide-binding activity, and its chaperone activity appeared to be substrate specific. Mutation analysis revealed that the first thioredoxin-like motif of P5 was more important than the second for isomerase activity, and that the first cysteine in each motif was necessary for isomerase activity. Thioredoxin motif mutants of P5 lacking isomerase activity retained chaperone activity with citrate synthase (CS; 118950) as substrate, indicating that, like PDI, the isomerase and chaperone activities of P5 are likely independent. Kaiser et al. (2007) showed that on the surface of tumor cells, MICA (600169) associates with ERP5, which, similar to protein disulfide isomerase (176790), usually assists in the folding of nascent proteins inside cells. Pharmacologic inhibition of thioreductase activity and ERP5 gene silencing revealed that cell-surface ERP5 function is required for MICA shedding. ERP5 and membrane-anchored MICA formed transitory mixed disulfide complexes from which soluble MICA was released after proteolytic cleavage near the cell membrane. Kaiser et al. (2007) suggested that reduction of the seemingly inaccessible disulfide bond in the membrane-proximal alpha-3 domain of MICA must involve a large conformational change that enables proteolytic cleavage. They concluded that their results uncovered a molecular mechanism whereby domain-specific deconstruction regulates MICA protein shedding, thereby promoting tumor immune evasion, and identified surface ERP5 as a strategic target for therapeutic intervention.MAPPING
By in situ hybridization, Yang-Feng et al. (1987) mapped the PDIA6 gene to chromosome 2p25-p24.ANIMAL MODEL
The zebrafish 'one-eyed pinhead' (oep) mutation is characterized by multiple deficiencies in midline development and a morphologically normal notochord. Hoshijima et al. (2002) found that P5 was expressed predominantly in the axial mesoderm of midgastrula wildtype embryos and was significantly downregulated in oep mutants. Functional analysis demonstrated that P5 was specifically involved in lateral patterning. Depletion of P5 protein with antisense morpholin ... More on the omim web site
Feb. 10, 2018: Protein entry updated
Automatic update: Entry updated from uniprot information.
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 611099 was added.
Jan. 25, 2016: Protein entry updated
Automatic update: model status changed