Protein disulfide-isomerase

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.[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.

Protein disulfide-isomerase

Structural picture of human protein disulfide isomerase (PDB 1BJX)
Identifiers
Symbol ?
InterPro IPR005792
Protein disulfide-isomerase
Identifiers
EC no. 5.3.4.1
CAS no. 37318-49-3
Databases
IntEnz IntEnz view
BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDBPDBePDBsum
Gene Ontology AmiGO / QuickGO
Search
PMC articles
PubMed articles
NCBI proteins
protein disulfide isomerase family A, member 2
Identifiers
Symbol PDIA2
Alt. symbols PDIP
NCBI gene 64714
HGNC 14180
OMIM 608012
RefSeq NM_006849
UniProt Q13087
Other data
Locus Chr. 16p13.3
Search for
Structures Swiss-model
Domains InterPro

protein disulfide isomerase family A, member 3
Identifiers
Symbol PDIA3
Alt. symbols GRP58
NCBI gene 2923
HGNC 4606
OMIM 602046
RefSeq NM_005313
UniProt P30101
Other data
Locus Chr. 15q15
Search for
Structures Swiss-model
Domains InterPro

protein disulfide isomerase family A, member 4
Identifiers
Symbol PDIA4
NCBI gene 9601
HGNC 30167
RefSeq NM_004911
UniProt P13667
Other data
Locus Chr. 7q35
Search for
Structures Swiss-model
Domains InterPro

protein disulfide isomerase family A, member 5
Identifiers
Symbol PDIA5
NCBI gene 10954
HGNC 24811
RefSeq NM_006810
UniProt Q14554
Other data
EC number 5.3.4.1
Locus Chr. 3q21.1
Search for
Structures Swiss-model
Domains InterPro

protein disulfide isomerase family A, member 6
Identifiers
Symbol PDIA6
Alt. symbols TXNDC7
NCBI gene 10130
HGNC 30168
RefSeq NM_005742
UniProt Q15084
Other data
Locus Chr. 2p25.1
Search for
Structures Swiss-model
Domains InterPro

. . . Protein disulfide-isomerase . . .

Protein disulfide-isomerase has two catalytic thioredoxin-like domains (active sites), each containing the canonical CGHC motif, and two non catalytic domains.[4][5][6] 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 CX9C, which is similar to the CGHC domain of PDI.[7] Bacterial DsbA, responsible for oxidative folding, also has a thioredoxin CXXC domain.[8]

Primary structure of protein disulfide isomerase with sequence of domains

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.[4] 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).[4]

PDI is specifically responsible for folding proteins in the ER.[6] In an unfolded protein, a cysteine residue forms a mixed disulfide with a cysteine residue in an active site (CGHC motif) of protein disulfide-isomerase. A second cysteine residue then forms a stable disulfide bridge within the substrate, leaving protein disulfide-isomerase’s two active-site cysteine residues in a reduced state.[4]

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).[4][9][10][6] 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.[10] Ero1 accepts electrons from PDI and donates these electrons to oxygen molecules in the ER, which leads to the formation of hydrogen peroxide.[10]

. . . Protein disulfide-isomerase . . .

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. . . Protein disulfide-isomerase . . .