Protein disulfide-isomerase

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Protein disulfide-isomerase
Identifiers
EC no.5.3.4.1
CAS no.37318-49-3
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO
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PMCarticles
PubMedarticles
NCBIproteins
protein disulfide isomerase family A, member 2
Identifiers
SymbolPDIA2
Alt. symbolsPDIP
NCBI gene64714
HGNC14180
OMIM608012
RefSeqNM_006849
UniProtQ13087
Other data
LocusChr. 16 p13.3
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StructuresSwiss-model
DomainsInterPro
protein disulfide isomerase family A, member 3
Identifiers
SymbolPDIA3
Alt. symbolsGRP58
NCBI gene2923
HGNC4606
OMIM602046
RefSeqNM_005313
UniProtP30101
Other data
LocusChr. 15 q15
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StructuresSwiss-model
DomainsInterPro
protein disulfide isomerase family A, member 4
Identifiers
SymbolPDIA4
NCBI gene9601
HGNC30167
RefSeqNM_004911
UniProtP13667
Other data
LocusChr. 7 q35
Search for
StructuresSwiss-model
DomainsInterPro
protein disulfide isomerase family A, member 5
Identifiers
SymbolPDIA5
NCBI gene10954
HGNC24811
RefSeqNM_006810
UniProtQ14554
Other data
EC number5.3.4.1
LocusChr. 3 q21.1
Search for
StructuresSwiss-model
DomainsInterPro
protein disulfide isomerase family A, member 6
Identifiers
SymbolPDIA6
Alt. symbolsTXNDC7
NCBI gene10130
HGNC30168
RefSeqNM_005742
UniProtQ15084
Other data
LocusChr. 2 p25.1
Search for
StructuresSwiss-model
DomainsInterPro

Protein disulfide isomerase or PDI is an enzyme in the endoplasmic reticulum in eukaryotes 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

Protein folding

PDI contains four thioredoxin-like domains, two of which retain the canonical CXXC motif. The reduced (dithiol) form of PDI is able to catalyse a reduction of mispaired thiol residues of a particular substrate, acting as an isomerase.[4] Therefore, PDI is capable of catalyzing the post-translational modification disulfide exchange. Such exchange reactions can occur intramolecularly, leading to the rearrangement of disulfide bonds in a single protein.[5][5]

Another major function of PDI relates to its activity as a chaperone; i.e., it aids wrongly folded proteins to reach a correctly folded state without the aid of enzymatic disulfide shuffling.

Oxidized PDI can catalyze the formation of a disulfide bridge. This reduces PDI, which is re-oxidized by a protein called Ero1.

Redox signaling

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]

Peptide binding

Other functions

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

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

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

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

References

  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 3500226. PMID 23245351.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  4. ^ 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.
  5. ^ a b Hatahet F, Ruddock LW (Nov 2009). "Protein disulfide isomerase: a critical evaluation of its function in disulfide bond formation". Antioxidants & Redox Signaling. 11 (11): 2807–50. doi:10.1089/ars.2009.2466.x. PMID 19476414.
  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. 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.
  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. 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 1299221. 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

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