Protein disulfide-isomerase (P4HB)
The protein contains 508 amino acids for an estimated molecular weight of 57116 Da.
This multifunctional protein catalyzes the formation, breakage and rearrangement of disulfide bonds. At the cell surface, seems to act as a reductase that cleaves disulfide bonds of proteins attached to the cell. May therefore cause structural modifications of exofacial proteins. Inside the cell, seems to form/rearrange disulfide bonds of nascent proteins. At high concentrations, functions as a chaperone that inhibits aggregation of misfolded proteins. At low concentrations, facilitates aggregation (anti-chaperone activity). May be involved with other chaperones in the structural modification of the TG precursor in hormone biogenesis. Also acts a structural subunit of various enzymes such as prolyl 4-hydroxylase and microsomal triacylglycerol transfer protein MTTP. Receptor for LGALS9; the interaction retains P4HB at the cell surface of Th2 T helper cells, increasing disulfide reductase activity at the plasma membrane, altering the plasma membrane redox state and enhancing cell migration (PubMed:21670307). (updated: Nov. 22, 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 |
|---|---|
| CLCRP1 |
Biological Process
Cell redox homeostasis
Cellular protein metabolic process
Cellular response to hypoxia
Cellular response to interleukin-7
Cellular response to oxidative stress
Chylomicron assembly
Collagen fibril organization
Extracellular matrix organization
Interleukin-12-mediated signaling pathway
Interleukin-23-mediated signaling pathway
Lipoprotein metabolic process
Peptidyl-proline hydroxylation to 4-hydroxy-L-proline
Positive regulation of cell adhesion
Positive regulation of substrate adhesion-dependent cell spreading
Positive regulation of viral entry into host cell
Post-translational protein modification
Protein folding
Protein folding in endoplasmic reticulum
Proteolysis
Regulation of oxidative stress-induced intrinsic apoptotic signaling pathway
Response to endoplasmic reticulum stress
Response to reactive oxygen species
Small molecule metabolic process
Very-low-density lipoprotein particle assembly
Cellular Component
Cytoskeleton
Cytosol
Endoplasmic reticulum
Endoplasmic reticulum chaperone complex
Endoplasmic reticulum lumen
Endoplasmic reticulum-Golgi intermediate compartment
External side of plasma membrane
Extracellular exosome
Extracellular matrix
Extracellular region
Focal adhesion
Lamellipodium
Melanosome
Obsolete cell
Plasma membrane
Procollagen-proline 4-dioxygenase complex
Protein-containing complex
Molecular Function
Actin binding
Endopeptidase activity
Enzyme binding
Integrin binding
Peptide disulfide oxidoreductase activity
Poly(A) RNA binding
Procollagen-proline 4-dioxygenase activity
Protein disulfide isomerase activity
Protein heterodimerization activity
RNA binding
Thiol oxidase activity
The reference OMIM entry for this protein is 176790
Procollagen-proline, 2-oxoglutarate-4-dioxygenase, beta subunit; p4hb
Prolyl 4-hydroxylase, beta subunit
Phdb; prohb; po4hb
Disulfide isomerase; dsi
Protein disulfide isomerase/oxidoreductase; pdi
Protein disulfide isomerase, family a, memb
CLONING
Prolyl 4-hydroxylase (EC 1.14.11.2) is involved in hydroxylation of prolyl residues in preprocollagen. Pihlajaniemi et al. (1987) cloned the PROHB gene. Prolyl 4-hydroxylase is a tetramer consisting of 2 alpha (176710, 600608) and 2 beta subunits of molecular weights about 64,000 and 60,000, respectively, for the monomers. Characterization of cDNA clones for the human beta subunit indicated that the polypeptide is 508 amino acids long, including a signal peptide of 17 amino acids. Pihlajaniemi et al. (1987) also found that disulfide isomerase (EC 5.3.4.1) is a product of the same gene. When present in cells in monomeric form, the protein serves the function of DSI (Koivu et al., 1987); when present in the prolyl 4-hydroxylase tetramer, it catalyzes the formation of 4-hydroxyproline in collagen. Cheng et al. (1987) demonstrated by molecular cloning and nucleotide sequencing that cellular thyroid hormone-binding protein is also identical to the beta subunit of prolyl 4-hydroxylase and protein disulfide isomerase. The protein disulfide isomerase/oxidoreductase (EC 1.8.4.2) is the same enzyme molecule as P4HB (Noiva and Lennarz, 1992). Also known as glutathione-insulin transhydrogenase, it catalyzes thiol:protein-disulfide interchange. GSH-insulin transhydrogenase is a ubiquitous, abundant protein that is located primarily in endoplasmic reticulum (ER), but is also associated with plasma membrane and other intracellular membrane compartments. Morris and Varandani (1988) determined the nucleotide sequence of a cDNA isolated from a human liver cDNA expression library in lambda phage gt11 with monoclonal antibodies to rat liver protein disulfide isomerase/oxidoreductase. The largest cDNA contained approximately 1,500 basepairs and represented an estimated 65% of the message. They found 100% identity with rat enzyme in the active site region and 81% similarity in other regions.GENE STRUCTURE
Tasanen et al. (1988) isolated genomic clones for the human gene coding for this multifunctional protein. They found that the gene is about 18 kb long and consists of 11 exons. The codons for the 2 presumed active sites of protein disulfide isomerase, each a cys-gly-his-cys sequence, were found to be located 12 bp from the beginning of exons 2 and 9.MAPPING
The P4HB gene was tentatively mapped to chromosome 7 by somatic cell hybridization (Pajunen et al., 1985). Pajunen et al. (1987, 1988) definitively assigned the gene for the beta subunit to chromosome 17, specifically, 17q23-q25. The identification in cell hybrids was performed by 3 different methods: immunoblotting using species-specific monoclonal antibodies, radioimmunoassay with species-specific polyclonal antibodies, and Southern blot analysis using cDNA for the human beta subunit. The sequence of the cellular thyroid hormone-binding protein with a molecular weight of 55,000 (p55) indicates that it is identical to protein disulfide isomerase and the beta subunit of prolyl 4-hydroxylase. By in situ hybridization, using a cDNA for the human p55 gene, Popescu et al. (1988) localized the gene to 17q25. This indicated that the p55 gene is not linked to either of the 2 other thyroid hormone-binding protein genes, ERBA1 (190120) and ERBA2 (190160), which are located at 17q11-q21 and 3pter-p21, respectively. Pajunen et al. (1991) confirmed the assignment of P4HB to 17q25 by in situ hybridization. Southern blot analysis of restricted DNA from a chromosome-mediated g ... 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 176790 was added.
Jan. 28, 2016: Protein entry updated
Automatic update: model status changed
Jan. 25, 2016: Protein entry updated
Automatic update: model status changed