Draft:Protein disulfide-isomerase

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Protein disulfide-isomerase
Identifiers
EC number 5.3.4.1
CAS number 37318-49-3
Databases
IntEnz IntEnz view
BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
Gene Ontology AmiGO / EGO
protein disulfide isomerase family A, member 2
Identifiers
Symbol PDIA2
Alt. symbols PDIP
Entrez 64714
HUGO 14180
OMIM 608012
RefSeq NM_006849
UniProt Q13087
Other data
Locus Chr. 16 p13.3
protein disulfide isomerase family A, member 3
Identifiers
Symbol PDIA3
Alt. symbols GRP58
Entrez 2923
HUGO 4606
OMIM 602046
RefSeq NM_005313
UniProt P30101
Other data
Locus Chr. 15 q15
protein disulfide isomerase family A, member 4
Identifiers
Symbol PDIA4
Entrez 9601
HUGO 30167
RefSeq NM_004911
UniProt P13667
Other data
Locus Chr. 7 q35
protein disulfide isomerase family A, member 5
Identifiers
Symbol PDIA5
Entrez 10954
HUGO 24811
RefSeq NM_006810
UniProt Q14554
Other data
EC number 5.3.4.1
Locus Chr. 3 q21.1
protein disulfide isomerase family A, member 6
Identifiers
Symbol PDIA6
Alt. symbols TXNDC7
Entrez 10130
HUGO 30168
RefSeq NM_005742
UniProt Q15084
Other data
Locus Chr. 2 p25.1

Protein disulfide isomerase or PDI is an enzyme in the endoplasmic reticulum in eukaryotes and the periplasm of bacteria that catalyzes the formation and breakage of disulfide bonds between cysteine residues within proteins as they fold.[1][2][3] 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.

Function[edit]

Protein folding[edit]

PDI contains two catalytic thioredoxin-like domains (a, a') containing the canonical CGHC motif and two non catalytic domains (b, b'); it displays oxidoreductase and isomerase activity, both of which depend on the type of substrate that binds to PDI and changes in PDI's redox state. For basic oxidative folding, the first substrate cysteine residue binds to the active site--either the a domain or the a' domain--of PDI to form an enzyme substate complex; a second substrate cysteine residue binds to the complex, whereby after subsequent catalysis, a stable disulfide bridge on the substrate is formed, leaving PDI's cysteine residues reduced. Afterwards, PDI is regenerated into its oxidized form by the ER's environment.[4] The reduced (dithiol) form of PDI is able to catalyze a reduction of misformed disulfide bridge of a particular substrate through either reductase activity or isomerase activity.[5] For the reductase method, misfolded substrate disulfide bonds are converted to reduced cysteine residues by the transfer of electrons from glutathione and NADPH. Afterwards, normal oxidative folding occurs to the correct pairs of substrate cysteine residues, leading to properly folded proteins. For the isomerase method, intramolecular rearrangement of substrate functional groups is catalyzed near the N terminus of the a/a' domain.[4] Therefore, PDI is capable of catalyzing the post-translational modification disulfide exchange.

Another major function of PDI relates to its activity as a chaperone; its b' domain aids in the binding of misfolded protein for subsequent degradation.[4]

Redox signaling[edit]

In the chloroplasts of the unicellular algae Chlamydomonas reinhardtii the PDI RB60 serves as a redox sensor component of an mRNA-binding protein complex implicated in the photo-regulation of the translation of psbA, the RNA encoding for the photosystem II core protein D1. PDI has also been suggested to play a role in the formation of regulatory disulfide bonds in chloroplasts.[6]

Other functions[edit]

PDI helps load antigenic peptides into MHC class I molecules. These molecules (MHC I) are related to the peptide presentation by antigen-presenting cells in the immune response.

PDI has been found to be involved in the breaking of bonds on the HIV gp120 protein during HIV infection of CD4 positive cells, and is required for HIV infection of lymphocytes and monocytes.[7] Some studies have shown it to be available for HIV infection on the surface of the cell clustered around the CD4 protein. Yet conflicting studies have shown that it is not available on the cell surface, but instead is found in significant amounts in the blood plasma.

PDI is critical for thrombus formation.[8]

Assays used for PDI activity[edit]

Insulin Turbidity Assay: PDI breaks the two disulfide bonds between two insulin (a and b) chains that results in precipitation of b chain. This precipitation can be monitored at 650 nm, which is indirectly used to monitor PDI activity.[9] Sensitivity of this assay is in micromolar range.

ScRNase assay: PDI converts scrambled (inactive) RNase into native (active) RNase that further acts on its substrate.[10] The sensitivity is in micromolar range.

Di-E-GSSG assay: This is the fluorometric assay that can detect picomolar quantities of PDI and therefore is the most sensitive assay to date for detecting PDI activity.[11] Di-E-GSSG has two eosin molecules attached to oxidized glutathione (GSSG). The proximity of eosin molecules leads to the quenching of its fluorescence. However, upon breakage of disulfide bond by PDI, fluorescence increases 70-fold.

Inhibition and Effects of Stress[edit]

Redox dysregulation leads to increases in nitrosative stress in the ER. Such adverse changes in the normal cellular environment of susceptible cells, such as neurons, leads to nonfunctioning PDIs. More specifically, PDI can no longer fix misfolded proteins once its thiol group in its active site has a nitric monoxide group attached to it; as a result, accumulation of misfolded proteins occurs in neurons, which leads to neurodegenerative diseases such as Alzheimer's Disease and Parkinson's Disease.[4]

Due to the role of PDI in a number of disease states, small molecule inhibitors of PDI have been developed. These molecules can either target the active site of PDI irreversibly [12] or reversibly.[13]

It has been shown that PDI activity is inhibited by red wine and grape juice, which could be the explanation for the French Paradox.[14]

Members[edit]

Human genes encoding Protein disulfide isomerases include:[3][15][16]

References[edit]

  1. ^ Wilkinson B, Gilbert HF (Jun 2004). "Protein disulfide isomerase". Biochimica et Biophysica Acta. 1699 (1–2): 35–44. doi:10.1016/j.bbapap.2004.02.017. PMID 15158710. 
  2. ^ Gruber CW, Cemazar M, Heras B, Martin JL, Craik DJ (Aug 2006). "Protein disulfide isomerase: the structure of oxidative folding". Trends in Biochemical Sciences. 31 (8): 455–64. doi:10.1016/j.tibs.2006.06.001. PMID 16815710. 
  3. ^ a b Galligan JJ, Petersen DR (July 2012). "The human protein disulfide isomerase gene family". Human Genomics. 6 (1): 6. doi:10.1186/1479-7364-6-6. PMC 3500226Freely accessible. PMID 23245351. 
  4. ^ a b c d Perri, Emma R.; Thomas, Colleen J.; Parakh, Sonam; Spencer, Damian M.; Atkin, Julie D. (2016). "The Unfolded Protein Response and the Role of Protein Disulfide Isomerase in Neurodegeneration". Frontiers in Cell and Developmental Biology. 3. doi:10.3389/fcell.2015.00080. ISSN 2296-634X. PMC 4705227Freely accessible. PMID 26779479. 
  5. ^ Hatahet F, Ruddock LW (Oct 2007). "Substrate recognition by the protein disulfide isomerases". The FEBS Journal. 274 (20): 5223–34. doi:10.1111/j.1742-4658.2007.06058.x. PMID 17892489. 
  6. ^ Wittenberg G, Danon A (2008). "Disulfide bond formation in chloroplasts". Plant Science. 175 (4): 459–466. doi:10.1016/j.plantsci.2008.05.011. 
  7. ^ Ryser HJ, Flückiger R (Aug 2005). "Progress in targeting HIV-1 entry". Drug Discovery Today. 10 (16): 1085–94. doi:10.1016/S1359-6446(05)03550-6. PMID 16182193. 
  8. ^ Flaumenhaft, Robert (2013). "Protein disulfide isomerase as an antithrombotic target". Trends in Cardiovascular Medicine. 23 (7): 264–268. doi:10.1016/j.tcm.2013.03.001. PMC 3701031Freely accessible. PMID 23541171. 
  9. ^ Lundström J, Holmgren A (Jun 1990). "Protein disulfide-isomerase is a substrate for thioredoxin reductase and has thioredoxin-like activity". The Journal of Biological Chemistry. 265 (16): 9114–20. PMID 2188973. 
  10. ^ Lyles MM, Gilbert HF (Jan 1991). "Catalysis of the oxidative folding of ribonuclease A by protein disulfide isomerase: dependence of the rate on the composition of the redox buffer". Biochemistry. 30 (3): 613–9. doi:10.1021/bi00217a004. PMID 1988050. 
  11. ^ Raturi A, Mutus B (Jul 2007). "Characterization of redox state and reductase activity of protein disulfide isomerase under different redox environments using a sensitive fluorescent assay". Free Radical Biology & Medicine. 43 (1): 62–70. doi:10.1016/j.freeradbiomed.2007.03.025. PMID 17561094. 
  12. ^ Hoffstrom BG, Kaplan A, Letso R, Schmid DC, Turmel RS, Lo GJ, Stockwell BR. "Inhibitors of protein disulfide isomerase suppress apoptosis induced by misfolded proteins" Nat". Chem. Biol. 2010 (12): 6. doi:10.1038/nchembio.467. 
  13. ^ Kaplan A, Gaschler MM, Dunn DE, Colligan R, Brown LM, Palmer AG, Lo DC, Stockwell BR (2015). "Small molecule induced oxidation of protein disulfide isomerase is neuroprotective". PNAS. 112: E2245–E2252. doi:10.1073/pnas.1500439112. PMC 4418888Freely accessible. PMID 25848045. 
  14. ^ Galinski, CN; et al. (2016). "Revisiting the mechanistic basis of the French Paradox: Red wine inhibits the activity of protein disulfide isomerase in vitro". Thrombosis Research. 137: 169–173. doi:10.1016/j.thromres.2015.11.003. PMID 26585763. 
  15. ^ Ellgaard L, Ruddock LW (Jan 2005). "The human protein disulphide isomerase family: substrate interactions and functional properties". EMBO Reports. 6 (1): 28–32. doi:10.1038/sj.embor.7400311. PMC 1299221Freely accessible. PMID 15643448. 
  16. ^ Appenzeller-Herzog C, Ellgaard L (Apr 2008). "The human PDI family: versatility packed into a single fold". Biochimica et Biophysica Acta. 1783 (4): 535–48. doi:10.1016/j.bbamcr.2007.11.010. PMID 18093543. 

External links[edit]