PDIA3

Last updated
PDIA3
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases PDIA3 , protein disulfide isomerase family A, member 3, ER60, ERp57, ERp60, ERp61, GRP57, GRP58, HEL-S-269, HEL-S-93n, HsT17083, P58, PI-PLC, protein disulfide isomerase family A member 3
External IDs OMIM: 602046 MGI: 95834 HomoloGene: 68454 GeneCards: PDIA3
Orthologs
SpeciesHumanMouse
Entrez

2923

14827

Ensembl

ENSG00000167004

ENSMUSG00000027248

UniProt

P30101

P27773

RefSeq (mRNA)

NM_005313

NM_007952

RefSeq (protein)

NP_005304

NP_031978

Location (UCSC) Chr 15: 43.75 – 43.77 Mb Chr 2: 121.24 – 121.27 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Protein disulfide-isomerase A3 (PDIA3), also known as glucose-regulated protein, 58-kD (GRP58), is an isomerase enzyme encoded by the autosomal gene PDIA3 in humans. [5] [6] [7] [8] This protein localizes to the endoplasmic reticulum (ER) and interacts with lectin chaperones calreticulin 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. [9]

Contents

Structure

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. [10] [11] 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. [11] 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. [10]

Function

The PDIA3 protein is a thiol oxidoreductase that has protein disulfide isomerase activity. [8] [10] PDIA3 is also part of the major histocompatibility complex (MHC) class I peptide loading complex, which is essential for formation of the final antigen conformation and export from the endoplasmic reticulum to the cell surface. [10] [12] This protein of the endoplasmic reticulum interacts with lectin chaperones such as calreticulin and CNX in order to modulate the folding of proteins that are newly synthesized. It is believed that PDIA3 plays a role in protein folding by promoting the formation of disulfide bonds, and that CNX facilitates the positioning substrates next to the catalytic cysteines. [9] [10] This function allows it to serve as a redox sensor by activating mTORC1, which then mediates mTOR complex assembly to adapt cells to oxidative damage. Thus, PDIA3 regulates cell growth and death according to oxygen concentrations, such as in the hypoxic microenvironment of bones. Additionally, PDIA3 activates cell anchorage in bones by associating with cell division and cytoskeleton proteins, such as beta-actin and vimentin, to form a complex which controls TUBB3 folding and proper attachment of the microtubules to the kinetochore. PDIA3 also plays a role in cytokine-dependent signal transduction, including STAT3 signaling. [13]

PDIA3 may also participate in Vitamin D (specifically, calcitriol) signaling as a membrane-bound receptor. [14]

Clinical significance

It has been demonstrated that the downregulation of ERp57 expression is correlated with poor prognosis in early-stage cervical cancer. [15] It has also been demonstrated that ERp57/PDIA3 binds specific DNA fragments in a melanoma cell line. [16] PDIA3 is also involved in bone metastasis, which is the most common source of distant relapse in breast cancer. [13] 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. [17]

Interactions

It has been demonstrated that PDIA3 interacts with:

See also

Related Research Articles

<span class="mw-page-title-main">Chaperone (protein)</span> Proteins assisting in protein folding

In molecular biology, molecular chaperones are proteins that assist the conformational folding or unfolding of large proteins or macromolecular protein complexes. There are a number of classes of molecular chaperones, all of which function to assist large proteins in proper protein folding during or after synthesis, and after partial denaturation. Chaperones are also involved in the translocation of proteins for proteolysis.

<span class="mw-page-title-main">Protein disulfide-isomerase</span> Class of enzymes

Protein disulfide isomerase, or PDI, is an enzyme in the endoplasmic reticulum (ER) in eukaryotes and the periplasm of bacteria that catalyzes the formation and breakage of disulfide bonds between cysteine residues within proteins as they fold. This allows proteins to quickly find the correct arrangement of disulfide bonds in their fully folded state, and therefore the enzyme acts to catalyze protein folding.

<span class="mw-page-title-main">Calnexin</span> Mammalian protein found in Homo sapiens

Calnexin (CNX) is a 67kDa integral protein of the endoplasmic reticulum (ER). It consists of a large N-terminal calcium-binding lumenal domain, a single transmembrane helix and a short, acidic cytoplasmic tail. In humans, calnexin is encoded by the gene CANX.

<span class="mw-page-title-main">Tissue transglutaminase</span> Protein-coding gene in the species Homo sapiens

Tissue transglutaminase is a 78-kDa, calcium-dependent enzyme of the protein-glutamine γ-glutamyltransferases family. Like other transglutaminases, it crosslinks proteins between an ε-amino group of a lysine residue and a γ-carboxamide group of glutamine residue, creating an inter- or intramolecular bond that is highly resistant to proteolysis. Aside from its crosslinking function, tTG catalyzes other types of reactions including deamidation, GTP-binding/hydrolyzing, and isopeptidase activities. Unlike other members of the transglutaminase family, tTG can be found both in the intracellular and the extracellular spaces of various types of tissues and is found in many different organs including the heart, the liver, and the small intestine. Intracellular tTG is abundant in the cytosol but smaller amounts can also be found in the nucleus and the mitochondria. Intracellular tTG is thought to play an important role in apoptosis. In the extracellular space, tTG binds to proteins of the extracellular matrix (ECM), binding particularly tightly to fibronectin. Extracellular tTG has been linked to cell adhesion, ECM stabilization, wound healing, receptor signaling, cellular proliferation, and cellular motility.

<span class="mw-page-title-main">ER oxidoreductin</span>

ER oxidoreductin 1 (Ero1) is an oxidoreductase enzyme that catalyses the formation and isomerization of protein disulfide bonds in the endoplasmic reticulum (ER) of eukaryotes. ER Oxidoreductin 1 (Ero1) is a conserved, luminal, glycoprotein that is tightly associated with the ER membrane, and is essential for the oxidation of protein dithiols. Since disulfide bond formation is an oxidative process, the major pathway of its catalysis has evolved to utilise oxidoreductases, which become reduced during the thiol-disulfide exchange reactions that oxidise the cysteine thiol groups of nascent polypeptides. Ero1 is required for the introduction of oxidising equivalents into the ER and their direct transfer to protein disulfide isomerase (PDI), thereby ensuring the correct folding and assembly of proteins that contain disulfide bonds in their native state.

<span class="mw-page-title-main">Endoplasmic-reticulum-associated protein degradation</span>

Endoplasmic-reticulum-associated protein degradation (ERAD) designates a cellular pathway which targets misfolded proteins of the endoplasmic reticulum for ubiquitination and subsequent degradation by a protein-degrading complex, called the proteasome.

The unfolded protein response (UPR) is a cellular stress response related to the endoplasmic reticulum (ER) stress. It has been found to be conserved between mammalian species, as well as yeast and worm organisms.

<span class="mw-page-title-main">Tapasin</span> Type of protein

TAP-associated glycoprotein, also known as tapasin or TAPBP, is a protein that in humans is encoded by the TAPBP gene.

<span class="mw-page-title-main">PPIB</span> Protein-coding gene in the species Homo sapiens

Peptidyl-prolyl cis-trans isomerase B is an enzyme that is encoded by the PPIB gene. As a member of the peptidyl-prolyl cis-trans isomerase (PPIase) family, this protein catalyzes the cis-trans isomerization of proline imidic peptide bonds, which allows it to regulate protein folding of type I collagen. Generally, PPIases are found in all eubacteria and eukaryotes, as well as in a few archaebacteria, and thus are highly conserved.

<span class="mw-page-title-main">Binding immunoglobulin protein</span> Protein-coding gene in the species Homo sapiens

Binding immunoglobulin protein (BiPS) also known as 78 kDa glucose-regulated protein (GRP-78) or heat shock 70 kDa protein 5 (HSPA5) is a protein that in humans is encoded by the HSPA5 gene.

<span class="mw-page-title-main">P4HB</span> Protein-coding gene in the species Homo sapiens

Protein disulfide-isomerase, also known as the beta-subunit of prolyl 4-hydroxylase (P4HB), is an enzyme that in humans encoded by the P4HB gene. The human P4HB gene is localized in chromosome 17q25. Unlike other prolyl 4-hydroxylase family proteins, this protein is multifunctional and acts as an oxidoreductase for disulfide formation, breakage, and isomerization. The activity of P4HB is tightly regulated. Both dimer dissociation and substrate binding are likely to enhance its enzymatic activity during the catalysis process.

<span class="mw-page-title-main">Microsomal triglyceride transfer protein</span> Large subunit of microsomal triglyceride transfer protein

Microsomal triglyceride transfer protein large subunit is a protein that in humans is encoded by the MTTP, also known as MTP, gene.

<span class="mw-page-title-main">ERP29</span> Protein-coding gene in humans

Endoplasmic reticulum protein 29 (ERp29) is a chaperone protein that in humans is encoded by the ERP29 gene.

<span class="mw-page-title-main">ERO1L</span> Protein-coding gene in the species Homo sapiens

ERO1-like protein alpha is a protein that in humans is encoded by the ERO1L gene.

<span class="mw-page-title-main">ERP44</span> Protein-coding gene in the species Homo sapiens

Endoplasmic reticulum resident protein 44 (ERp44) also known as thioredoxin domain-containing protein 4 (TXNDC4) is a protein that in humans is encoded by the ERP44 gene.

<span class="mw-page-title-main">TXNDC5</span> Protein-coding gene in the species Homo sapiens

Thioredoxin domain-containing protein 5 is a protein that in humans is encoded by the TXNDC5 gene.

<span class="mw-page-title-main">DsbA</span>

DsbA is a bacterial thiol disulfide oxidoreductase (TDOR). DsbA is a key component of the Dsb family of enzymes. DsbA catalyzes intrachain disulfide bond formation as peptides emerge into the cell's periplasm.

Thioredoxins are small disulfide-containing redox proteins that have been found in all the kingdoms of living organisms. Thioredoxin serves as a general protein disulfide oxidoreductase. It interacts with a broad range of proteins by a redox mechanism based on reversible oxidation of 2 cysteine thiol groups to a disulfide, accompanied by the transfer of 2 electrons and 2 protons. The net result is the covalent interconversion of a disulfide and a dithiol.

<span class="mw-page-title-main">PDIA2</span> Protein-coding gene in the species Homo sapiens

Protein disulfide isomerase family A member 2 is a protein that in humans is encoded by the PDIA2 gene.

<span class="mw-page-title-main">Peptide loading complex</span>

The peptide-loading complex (PLC) is a short-lived, multisubunit membrane protein complex that is located in the endoplasmic reticulum (ER). It orchestrates peptide translocation and selection by major histocompatibility complex class I (MHC-I) molecules. Stable peptide-MHC I complexes are released to the cell surface to promote T-cell response against malignant or infected cells. In turn, T-cells recognize the activated peptides, which could be immunogenic or non-immunogenic.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000167004 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000027248 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ "Symbol report for PDIA3". HGNC. HUGO Gene Nomenclature Committee. Retrieved 7 February 2024.
  6. ↑ Bourdi M, Demady D, Martin JL, Jabbour SK, Martin BM, George JW, Pohl LR (Nov 1995). "cDNA cloning and baculovirus expression of the human liver endoplasmic reticulum P58: characterization as a protein disulfide isomerase isoform, but not as a protease or a carnitine acyltransferase". Archives of Biochemistry and Biophysics. 323 (2): 397–403. doi: 10.1006/abbi.1995.0060 . PMID   7487104.
  7. ↑ Hirano N, Shibasaki F, Sakai R, Tanaka T, Nishida J, Yazaki Y, Takenawa T, Hirai H (Nov 1995). "Molecular cloning of the human glucose-regulated protein ERp57/GRP58, a thiol-dependent reductase. Identification of its secretory form and inducible expression by the oncogenic transformation". European Journal of Biochemistry. 234 (1): 336–42. doi:10.1111/j.1432-1033.1995.336_c.x. PMID   8529662.
  8. 1 2 Koivunen P, Helaakoski T, Annunen P, Veijola J, Räisänen S, Pihlajaniemi T, Kivirikko KI (Jun 1996). "ERp60 does not substitute for protein disulphide isomerase as the beta-subunit of prolyl 4-hydroxylase". The Biochemical Journal. 316. 316 (2): 599–605. doi:10.1042/bj3160599. PMC   1217390 . PMID   8687406.
  9. 1 2 "Entrez Gene: PDIA3 protein disulfide isomerase family A, member 3".
  10. 1 2 3 4 5 6 Dong G, Wearsch PA, Peaper DR, Cresswell P, Reinisch KM (Jan 2009). "Insights into MHC class I peptide loading from the structure of the tapasin-ERp57 thiol oxidoreductase heterodimer". Immunity. 30 (1): 21–32. doi:10.1016/j.immuni.2008.10.018. PMC   2650231 . PMID   19119025.
  11. 1 2 3 4 Kozlov G, Maattanen P, Schrag JD, Pollock S, Cygler M, Nagar B, Thomas DY, Gehring K (Aug 2006). "Crystal structure of the bb' domains of the protein disulfide isomerase ERp57". Structure. 14 (8): 1331–9. doi: 10.1016/j.str.2006.06.019 . PMID   16905107.
  12. ↑ Garbi N, Tanaka S, Momburg F, Hämmerling GJ (Jan 2006). "Impaired assembly of the major histocompatibility complex class I peptide-loading complex in mice deficient in the oxidoreductase ERp57". Nature Immunology. 7 (1): 93–102. doi:10.1038/ni1288. PMID   16311600. S2CID   5857455.
  13. 1 2 Santana-Codina N, Carretero R, Sanz-Pamplona R, Cabrera T, Guney E, Oliva B, Clezardin P, Olarte OE, Loza-Alvarez P, Méndez-Lucas A, Perales JC, Sierra A (Aug 2013). "A transcriptome-proteome integrated network identifies endoplasmic reticulum thiol oxidoreductase (ERp57) as a hub that mediates bone metastasis". Molecular & Cellular Proteomics. 12 (8): 2111–25. doi: 10.1074/mcp.M112.022772 . PMC   3734573 . PMID   23625662.
  14. ↑ Gaucci E, Raimondo D, Grillo C, Cervoni L, Altieri F, Nittari G, et al. (November 2016). "Analysis of the interaction of calcitriol with the disulfide isomerase ERp57". Scientific Reports. 6: 37957. Bibcode:2016NatSR...637957G. doi:10.1038/srep37957. PMC   5126700 . PMID   27897272.
  15. ↑ Chung H, Cho H, Perry C, Song J, Ylaya K, Lee H, Kim JH (Nov 2013). "Downregulation of ERp57 expression is associated with poor prognosis in early-stage cervical cancer". Biomarkers. 18 (7): 573–9. doi:10.3109/1354750X.2013.827742. PMID   23957851. S2CID   23970844.
  16. ↑ Aureli C, Gaucci E, Arcangeli V, Grillo C, Eufemi M, Chichiarelli S (Jul 2013). "ERp57/PDIA3 binds specific DNA fragments in a melanoma cell line". Gene. 524 (2): 390–5. doi:10.1016/j.gene.2013.04.004. hdl:11573/516861. PMID   23587917.
  17. ↑ Dihazi H, Dihazi GH, Bibi A, Eltoweissy M, Mueller CA, Asif AR, Rubel D, Vasko R, Mueller GA (Aug 2013). "Secretion of ERP57 is important for extracellular matrix accumulation and progression of renal fibrosis, and is an early sign of disease onset". Journal of Cell Science. 126 (Pt 16): 3649–63. doi: 10.1242/jcs.125088 . PMID   23781031.
  18. 1 2 3 4 Leach MR, Cohen-Doyle MF, Thomas DY, Williams DB (Aug 2002). "Localization of the lectin, ERp57 binding, and polypeptide binding sites of calnexin and calreticulin". The Journal of Biological Chemistry. 277 (33): 29686–97. doi: 10.1074/jbc.M202405200 . PMID   12052826.
  19. ↑ Alanen HI, Williamson RA, Howard MJ, Hatahet FS, Salo KE, Kauppila A, Kellokumpu S, Ruddock LW (Nov 2006). "ERp27, a new non-catalytic endoplasmic reticulum-located human protein disulfide isomerase family member, interacts with ERp57". The Journal of Biological Chemistry. 281 (44): 33727–38. doi: 10.1074/jbc.M604314200 . PMID   16940051.
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