View source for Protein disulfide-isomerase

[[File:PDB 1bjx EBI.jpg|thumb|370x370px|Structural picture of human protein disulfide isomerase 
(PDB ID: 1BJX)
]]
{{enzyme
| Name = Protein disulfide-isomerase
| EC_number = 5.3.4.1
| CAS_number = 37318-49-3
| IUBMB_EC_number = 5/3/4/1
| GO_code = 0003756
| image = 
| width = 
| caption = 
}}
{{infobox protein
| Name = protein disulfide isomerase family A, member 2
| caption = 
| image = 
| width = 
| HGNCid = 14180
| Symbol = [[PDIA2]]
| AltSymbols = PDIP
| EntrezGene = 64714
| OMIM = 608012
| RefSeq = NM_006849
| UniProt = Q13087
| PDB = 
| ECnumber = 
| Chromosome = 16
| Arm = p
| Band = 13.3
| LocusSupplementaryData = 
}}
{{infobox protein
| Name = [[PDIA3|protein disulfide isomerase family A, member 3]]
| caption = 
| image = 
| width = 
| HGNCid = 4606
| Symbol = [[PDIA3]]
| AltSymbols = GRP58
| EntrezGene = 2923
| OMIM = 602046
| RefSeq = NM_005313
| UniProt = P30101
| PDB = 
| ECnumber = 
| Chromosome = 15
| Arm = q
| Band = 15
| LocusSupplementaryData = 
}}
{{infobox protein
| Name = protein disulfide isomerase family A, member 4
| caption = 
| image = 
| width = 
| HGNCid = 30167
| Symbol = [[PDIA4]]
| AltSymbols = 
| EntrezGene = 9601
| OMIM = 
| RefSeq = NM_004911
| UniProt = P13667
| PDB = 
| ECnumber = 
| Chromosome = 7
| Arm = q
| Band = 35
| LocusSupplementaryData = 
}}
{{infobox protein
| Name = protein disulfide isomerase family A, member 5
| caption = 
| image = 
| width = 
| HGNCid = 24811
| Symbol = [[PDIA5]]
| AltSymbols = 
| EntrezGene = 10954
| OMIM = 
| RefSeq = NM_006810
| UniProt = Q14554
| PDB = 
| ECnumber = 5.3.4.1
| Chromosome = 3
| Arm = q
| Band = 21.1
| LocusSupplementaryData = 
}}
{{infobox protein
| Name = protein disulfide isomerase family A, member 6
| caption = 
| image = 
| width = 
| HGNCid = 30168
| Symbol = [[PDIA6]]
| AltSymbols = TXNDC7
| EntrezGene = 10130
| OMIM = 
| RefSeq = NM_005742
| UniProt = Q15084
| PDB = 
| ECnumber = 
| Chromosome = 2
| Arm = p
| Band = 25.1
| LocusSupplementaryData = 
}}
'''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 bond]]s between [[cysteine]] residues within [[protein]]s as they fold.<ref name="pmid15158710">{{cite journal | vauthors = Wilkinson B, Gilbert HF | title = Protein disulfide isomerase | journal = Biochimica et Biophysica Acta | volume = 1699 | issue = 1–2 | pages = 35–44 | date = Jun 2004 | pmid = 15158710 | doi = 10.1016/j.bbapap.2004.02.017 }}</ref><ref name="pmid16815710">{{cite journal | vauthors = Gruber CW, Cemazar M, Heras B, Martin JL, Craik DJ | title = Protein disulfide isomerase: the structure of oxidative folding | journal = Trends in Biochemical Sciences | volume = 31 | issue = 8 | pages = 455–64 | date = Aug 2006 | pmid = 16815710 | doi = 10.1016/j.tibs.2006.06.001 }}</ref><ref name="humgenomics.com">{{cite journal | vauthors = Galligan JJ, Petersen DR | title = The human protein disulfide isomerase gene family | journal = Human Genomics | volume = 6 | issue = 1 | date = July 2012 | pmid = 23245351 | pmc = 3500226 | doi = 10.1186/1479-7364-6-6 | url = http://www.humgenomics.com/content/6/1/6 | pages=6}}</ref>  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]].

== Structure ==
Protein disulfide-isomerase has two catalytic [[thioredoxin]]-like [[Protein domain|domains]] (active sites), each containing the canonical CGHC motif, and two non catalytic domains.<ref name=":0">{{Cite journal|last=Perri|first=Emma R.|last2=Thomas|first2=Colleen J.|last3=Parakh|first3=Sonam|last4=Spencer|first4=Damian M.|last5=Atkin|first5=Julie D.|date=2016|title=The Unfolded Protein Response and the Role of Protein Disulfide Isomerase in Neurodegeneration|url=http://journal.frontiersin.org/article/10.3389/fcell.2015.00080/full|journal=Frontiers in Cell and Developmental Biology|language=English|volume=3|doi=10.3389/fcell.2015.00080|issn=2296-634X|pmc=4705227|pmid=26779479}}</ref><ref name=":1">{{Cite journal|last=Bechtel|first=Tyler J.|last2=Weerapana|first2=Eranthie|date=2017-03-01|title=From structure to redox: The diverse functional roles of disulfides and implications in disease|url=http://onlinelibrary.wiley.com/doi/10.1002/pmic.201600391/abstract|journal=PROTEOMICS|language=en|volume=17|issue=6|pages=n/a–n/a|doi=10.1002/pmic.201600391|issn=1615-9861|pmc=5367942|pmid=28044432}}</ref><ref name=":4">{{Cite journal|last=Soares Moretti|first=Ana Iochabel|last2=Martins Laurindo|first2=Francisco Rafael|date=2017-03-01|title=Protein disulfide isomerases: Redox connections in and out of the endoplasmic reticulum|url=http://www.sciencedirect.com/science/article/pii/S0003986116305215|journal=Archives of Biochemistry and Biophysics|series=The Chemistry of Redox Signaling|volume=617|pages=106–119|doi=10.1016/j.abb.2016.11.007}}</ref> This structure is similar to the structure of enzymes responsible for oxidative folding in the intermembrane space of the mitochondria; an example of this is mitochondrial IMS import and assembly (Mia40), which has 2 catalytic domains that contain a CX<sub>9</sub>C, which is similar to the CGHC domain of PDI.<ref>{{Cite journal|last=Erdogan|first=Alican J.|last2=Riemer|first2=Jan|date=2017-01-01|title=Mitochondrial disulfide relay and its substrates: mechanisms in health and disease|url=https://link.springer.com/article/10.1007/s00441-016-2481-z|journal=Cell and Tissue Research|language=en|volume=367|issue=1|pages=59–72|doi=10.1007/s00441-016-2481-z|issn=0302-766X}}</ref>
[[File:Primary Struture PDI Cropped.png|none|thumb|578x578px|Primary structure of protein disulfide isomerase with sequence of domains]]

== Function ==

===Protein folding===

PDI displays [[oxidoreductase]] and [[isomerase]] properties, both of which depend on the type of substrate that binds to protein disulfide-isomerase and changes in protein disulfide-isomerase's redox state.<ref name=":0" /> These types of activities allow for oxidative folding of proteins. Oxidative folding involves the oxidation of reduced cysteine residues of nascent proteins; upon oxidation of these cysteine residues, disulfide bridges are formed, which stabilizes proteins and allows for native structures (namely tertiary and quaternary structures).<ref name=":1" />

'''Regular Oxidative Folding Mechanism and Pathway'''

PDI is specifically responsible for folding proteins for the ER, which are first translated in the cytosol by free ribosomes.<ref name=":4" /> For each unfolded protein, the first cysteine residue binds to either active site (CGHC motif) of protein disulfide-isomerase to form an enzyme substate complex; a second cysteine residue binds to the complex, whereby after subsequent catalysis, a stable disulfide bridge on the [[Substrate (chemistry)|substrate]] is formed, leaving protein disulfide-isomerase's cysteine residues reduced.<ref name=":0" /><ref name=":1" /> 
[[File:PDI Folding Pathway.png|thumb|center|500x500px|Figure1: Folding pathway of PDI]]

Afterwards, PDI can be regenerated to its oxidized form in the [[endoplasmic reticulum]] by transferring electrons to reoxidizing proteins such ER Oxidoreductin 1 (Ero 1), VKOR (vitamin K epoxide reductase), glutathione peroxidase (Gpx7/8), and PrxIV (peroxiredoxin IV).<ref name=":0" /><ref>{{Cite journal|last=Manganas|first=Phanee|last2=MacPherson|first2=Lisa|last3=Tokatlidis|first3=Kostas|date=2017-01-01|title=Oxidative protein biogenesis and redox regulation in the mitochondrial intermembrane space|url=https://link.springer.com/article/10.1007/s00441-016-2488-5|journal=Cell and Tissue Research|language=en|volume=367|issue=1|pages=43–57|doi=10.1007/s00441-016-2488-5|issn=0302-766X|pmc=5203823|pmid=27632163}}</ref><ref name=":2">{{Cite journal|last=Oka|first=Ojore B. V.|last2=Yeoh|first2=Hui Y.|last3=Bulleid|first3=Neil J.|date=2015-07-15|title=Thiol-disulfide exchange between the PDI family of oxidoreductases negates the requirement for an oxidase or reductase for each enzyme|url=http://www.biochemj.org/content/469/2/279|journal=Biochemical Journal|language=en|volume=469|issue=2|pages=279–288|doi=10.1042/bj20141423|issn=0264-6021|pmid=25989104}}</ref><ref name=":4" /> Ero1 is thought to be the main reoxidizing protein of PDI, and the pathway of reoxidation of PDI for Ero1 is more understood than that of other proteins.<ref name=":2" /> Ero1 accepts electrons from PDI and donates these electrons to oxygen molecules in the ER, which leads to the formation of hydrogen peroxide.<ref name=":2" />

==== Misfolded Protein Mechanism ====
The reduced (dithiol) form of protein disulfide-isomerase is able to catalyze a reduction of misformed disulfide bridge of a particular substrate through either reductase activity or isomerase activity.<ref name="pmid17892489">{{cite journal | vauthors = Hatahet F, Ruddock LW | title = Substrate recognition by the protein disulfide isomerases | journal = The FEBS Journal | volume = 274 | issue = 20 | pages = 5223–34 | date = Oct 2007 | pmid = 17892489 | doi = 10.1111/j.1742-4658.2007.06058.x }}</ref> 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 each active site.<ref name=":0" /> Therefore, protein disulfide-isomerase is capable of catalyzing the [[post-translational modification]] [[Disulfide bond|disulfide exchange]].

=== Redox signaling ===

In the [[chloroplast]]s of the unicellular [[algae]] ''[[Chlamydomonas reinhardtii]]'' the protein disulfide-isomerase RB60 serves as a redox sensor component of an m[[RNA-binding protein]] complex implicated in the [[photoregulation]] of the translation of psbA, the RNA encoding for the photosystem II core protein D1. Protein disulfide-isomerase has also been suggested to play a role in the formation of regulatory disulfide bonds in chloroplasts.<ref name="pmid100">{{cite journal | vauthors =Wittenberg G, Danon A | title = Disulfide bond formation in chloroplasts | journal = Plant Science | volume = 175 | issue = 4 | pages = 459–466 | year = 2008| doi = 10.1016/j.plantsci.2008.05.011 | url =  }}</ref>

=== Other functions ===

==== Immune System ====
Protein disulfide-isomerase helps load [[antigenic peptide]]s into [[MHC class I]] molecules.  These molecules (MHC I) are related to the peptide presentation by [[antigen-presenting cell]]s in the [[immune response]].

Protein disulfide-isomerase 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 [[lymphocyte]]s and monocytes.<ref name=Ryser2005>{{cite journal | vauthors = Ryser HJ, Flückiger R | title = Progress in targeting HIV-1 entry | journal = Drug Discovery Today | volume = 10 | issue = 16 | date = Aug 2005 | pmid = 16182193 | doi = 10.1016/S1359-6446(05)03550-6 | pages=1085–94}}</ref> 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.

==== Chaperone Activity ====
Another major function of protein disulfide-isomerase relates to its activity as a [[Chaperone (protein)|chaperone]]; its b' domain aids in the binding of [[misfolded]] protein for subsequent [[Biodegradation|degradation]].<ref name=":0" /> This is regulated by three ER membrane proteins, Protein Kinase RNA-like endoplasmic reticulum kinase (PERK), inositol-requiring kinase 1 (IRE1), and activating transcription factor 6 (ATF6).<ref name=":0" /><ref name=":3">{{Cite journal|last=McBean|first=G J|last2=López|first2=M G|last3=Wallner|first3=F K|date=2017-06-01|title=Redox-based therapeutics in neurodegenerative disease|url=http://onlinelibrary.wiley.com/doi/10.1111/bph.13551/abstract|journal=British Journal of Pharmacology|language=en|volume=174|issue=12|pages=1750–1770|doi=10.1111/bph.13551|issn=1476-5381|pmc=5446580|pmid=27477685}}</ref> They respond to high levels of misfolded proteins in the ER through intracellular signaling cascades that can activate PDI's chaperone activity.<ref name=":0" /> These signals can also inactivate translation of these misfolded proteins, because the cascade travels from the ER to the nucleus.<ref name=":0" />

== Activity assays ==

''Insulin Turbidity Assay'': protein disulfide-isomerase 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&nbsp;nm, which is indirectly used to monitor protein disulfide-isomerase activity.<ref>{{cite journal | vauthors = Lundström J, Holmgren A | title = Protein disulfide-isomerase is a substrate for thioredoxin reductase and has thioredoxin-like activity | journal = The Journal of Biological Chemistry | volume = 265 | issue = 16 | pages = 9114–20 | date = Jun 1990 | pmid = 2188973 }}</ref> Sensitivity of this assay is in micromolar range.

''ScRNase assay'': protein disulfide-isomerase converts scrambled (inactive) [[RNase]] into native (active) RNase that further acts on its substrate.<ref>{{cite journal | vauthors = Lyles MM, Gilbert HF | title = Catalysis of the oxidative folding of ribonuclease A by protein disulfide isomerase: dependence of the rate on the composition of the redox buffer | journal = Biochemistry | volume = 30 | issue = 3 | pages = 613–9 | date = Jan 1991 | pmid = 1988050 | doi = 10.1021/bi00217a004 }}</ref> The sensitivity is in micromolar range.

''Di-E-GSSG assay'': This is the [[enzyme assay#Fluorimetric|fluorometric assay]] that can detect [[picomolar]] quantities of protein disulfide-isomerase and therefore is the most sensitive assay to date for detecting protein disulfide-isomerase activity.<ref>{{cite journal | vauthors = Raturi A, Mutus B | title = Characterization of redox state and reductase activity of protein disulfide isomerase under different redox environments using a sensitive fluorescent assay | journal = Free Radical Biology & Medicine | volume = 43 | issue = 1 | pages = 62–70 | date = Jul 2007 | pmid = 17561094 | doi = 10.1016/j.freeradbiomed.2007.03.025 }}</ref> Di-E-GSSG has two [[eosin]] molecules attached to oxidized [[glutathione]] (GSSG).  The proximity of eosin molecules leads to the [[quenching (fluorescence)|quenching]] of its fluorescence. However, upon breakage of disulfide bond by protein disulfide-isomerase, fluorescence increases 70-fold.

==Stress and Inhibition==

=== Effects of Nitrosative Stress ===
Redox dysregulation leads to increases in [[nitrosative stress]] in the endoplasmic reticulum. Such adverse changes in the normal cellular environment of susceptible cells, such as neurons, leads to nonfunctioning thiol-containing enzymes.<ref name=":3" /> More specifically, protein disulfide-isomerase 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 has been associated with the defelopment of neurodegenerative diseases such as Alzheimer's Disease and Parkinson's Disease.<ref name=":0" /><ref name=":3" />

=== Inhibition ===
Due to the role of protein disulfide-isomerase in a number of disease states, small molecule inhibitors of protein disulfide-isomerase have been developed. These molecules can either target the active site of protein disulfide-isomerase irreversibly<ref>{{cite journal | vauthors = Hoffstrom BG, Kaplan A, Letso R, Schmid DC, Turmel RS, Lo GJ, Stockwell BR | year = | title = Inhibitors of protein disulfide isomerase suppress apoptosis induced by misfolded proteins" Nat | url = | journal = Chem. Biol. | volume = 2010 | issue = 12| page = 6 | doi = 10.1038/nchembio.467 }}</ref> or reversibly.<ref>{{cite journal | vauthors = Kaplan A, Gaschler MM, Dunn DE, Colligan R, Brown LM, Palmer AG, Lo DC, Stockwell BR | year = 2015 | title = Small molecule induced oxidation of protein disulfide isomerase is neuroprotective | journal = PNAS | volume = 112| issue = | pages = E2245–E2252| doi = 10.1073/pnas.1500439112 | pmid=25848045 | pmc=4418888}}</ref>

It has been shown that protein disulfide-isomerase activity is inhibited by red wine and grape juice, which could be the explanation for the [[French Paradox]].<ref>{{cite journal|last1=Galinski|first1=CN|title=Revisiting the mechanistic basis of the French Paradox: Red wine inhibits the activity of protein disulfide isomerase in vitro|journal=Thrombosis Research|date=2016|volume=137|pages=169–173|pmid=26585763|display-authors=etal|doi=10.1016/j.thromres.2015.11.003}}</ref>

== Members ==

[[Human gene]]s encoding protein disulfide isomerases include:<ref name="humgenomics.com"/><ref name="pmid15643448">{{cite journal | vauthors = Ellgaard L, Ruddock LW | title = The human protein disulphide isomerase family: substrate interactions and functional properties | journal = EMBO Reports | volume = 6 | issue = 1 | pages = 28–32 | date = Jan 2005 | pmid = 15643448 | pmc = 1299221 | doi = 10.1038/sj.embor.7400311 }}</ref><ref name="pmid18093543">{{cite journal | vauthors = Appenzeller-Herzog C, Ellgaard L | title = The human PDI family: versatility packed into a single fold | journal = Biochimica et Biophysica Acta | volume = 1783 | issue = 4 | pages = 535–48 | date = Apr 2008 | pmid = 18093543 | doi = 10.1016/j.bbamcr.2007.11.010 }}</ref>
{{div col|colwidth=10em}}
* [[AGR2]]
* [[AGR3]]
* [[CASQ1]]
* [[CASQ2]]
* [[DNAJC10]]
* [[ERP27]]
* [[ERP29]]
* [[ERP44]]
* [[P4HB]]
* [[PDIA2]]
* [[PDIA3]]
* [[PDIA4]]
* [[PDIA5]]
* [[PDIA6]]
* [[PDIALT]]
* [[TMX1]]
* [[TMX2]]
* [[TMX3]]
* [[TMX4]]
* [[TXNDC5]]
* [[TXNDC12]]
{{Div col end}}

== References ==
{{reflist|33em}}

== External links ==
* {{MeshName|Protein+Disulfide-Isomerase|3=Protein Disulfide-Isomerase}}

{{Intramolecular oxidoreductases}}
{{Enzymes}}
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{{improve categories|date=June 2017}}

[[Category:EC 5.3.4]]
[[Category:Proteins]]