DB code: M00184

CATH domain -.-.-.- :
1.25.40.10 : Serine Threonine Protein Phosphatase 5, Tetratricopeptide repeat
-.-.-.- :
2.60.-.- :
3.40.30.10 : Glutaredoxin Catalytic domain
3.40.30.10 : Glutaredoxin
3.40.30.10 : Glutaredoxin
3.40.30.10 : Glutaredoxin Catalytic domain
-.-.-.- :
E.C. 1.14.11.2 5.3.4.1
CSA 1mek
M-CSA 1mek
MACiE M0191

CATH domain Related DB codes (homologues)
3.40.30.10 : Glutaredoxin S00916 S00279 D00866 D00869 D00870 D00278
1.25.40.10 : Serine Threonine Protein Phosphatase 5, Tetratricopeptide repeat D00469

Uniprot Enzyme Name
UniprotKB Protein name Synonyms RefSeq Pfam
P13674 Prolyl 4-hydroxylase subunit alpha-1
4-PH alpha-1
EC 1.14.11.2
Procollagen-proline,2-oxoglutarate-4-dioxygenase subunit alpha-1
NP_000908.2 (Protein)
NM_000917.3 (DNA/RNA sequence)
NP_001017962.1 (Protein)
NM_001017962.2 (DNA/RNA sequence)
NP_001136067.1 (Protein)
NM_001142595.1 (DNA/RNA sequence)
NP_001136068.1 (Protein)
NM_001142596.1 (DNA/RNA sequence)
PF03171 (2OG-FeII_Oxy)
PF08336 (P4Ha_N)
[Graphical View]
P07237 Protein disulfide-isomerase
PDI
EC 5.3.4.1
Cellular thyroid hormone-binding protein
Prolyl 4-hydroxylase subunit beta
p55
NP_000909.2 (Protein)
NM_000918.3 (DNA/RNA sequence)
PF00085 (Thioredoxin)
[Graphical View]

KEGG enzyme name
procollagen-proline dioxygenase
(EC 1.14.11.2 )
protocollagen hydroxylase
(EC 1.14.11.2 )
proline hydroxylase
(EC 1.14.11.2 )
proline,2-oxoglutarate 4-dioxygenase
(EC 1.14.11.2 )
collagen proline hydroxylase
(EC 1.14.11.2 )
hydroxylase, collagen proline
(EC 1.14.11.2 )
peptidyl proline hydroxylase
(EC 1.14.11.2 )
proline protocollagen hydroxylase
(EC 1.14.11.2 )
proline, 2-oxoglutarate dioxygenase
(EC 1.14.11.2 )
prolyl hydroxylase
(EC 1.14.11.2 )
prolylprotocollagen dioxygenase
(EC 1.14.11.2 )
prolylprotocollagen hydroxylase
(EC 1.14.11.2 )
protocollagen proline 4-hydroxylase
(EC 1.14.11.2 )
protocollagen proline dioxygenase
(EC 1.14.11.2 )
protocollagen proline hydroxylase
(EC 1.14.11.2 )
protocollagen prolyl hydroxylase
(EC 1.14.11.2 )
prolyl 4-hydroxylase
(EC 1.14.11.2 )
prolyl-glycyl-peptide, 2-oxoglutarate:oxygen oxidoreductase,4-hydroxylating
(EC 1.14.11.2 )
procollagen-proline 4-dioxygenase
(EC 1.14.11.2 )
protein disulfide-isomerase
(EC 5.3.4.1 )
S-S rearrangase
(EC 5.3.4.1 )

UniprotKB: Accession Number Entry name Activity Subunit Subcellular location Cofactor
P07237 PDIA1_HUMAN Catalyzes the rearrangement of -S-S- bonds in proteins. Homodimer. Monomers and homotetramers may also occur. Also constitutes the structural subunit of prolyl 4-hydroxylase and of the microsomal triacylglycerol transfer protein MTTP in mammalian cells. Stabilizes both enzymes and retain them in the ER without contributing to the catalytic activity (By similarity). Binds UBQLN1. Binds to CD4, and upon HIV-1 binding to the cell membrane, is part of a P4HB/PDI-CD4-CXCR4-gp120 complex. Endoplasmic reticulum lumen. Melanosome. Cell membrane, Peripheral membrane protein (Potential). Note=Highly abundant. In some cell types, seems to be also secreted or associated with the plasma membrane, where it undergoes constant shedding and replacement from intracellular sources (Probable). Localizes near CD4-enriched regions on lymphoid cell surfaces. Identified by mass spectrometry in melanosome fractions from stage I to stage IV.
P13674 P4HA1_HUMAN Procollagen L-proline + 2-oxoglutarate + O(2) = procollagen trans-4-hydroxy-L-proline + succinate + CO(2). Heterotetramer of two alpha-1 chains and two beta chains (the beta chain is the multi-functional PDI). Endoplasmic reticulum lumen. Binds 1 Fe(2+) ion per subunit. Ascorbate.

KEGG Pathways
Map code Pathways E.C.
MAP00330 Arginine and proline metabolism 1.14.11.2

Compound table
Cofactors Substrates Products Intermediates
KEGG-id C00023 C00072 C01078 C00026 C00007 C00148 C02461 C04398 C00042 C00011 C02461
E.C. 1.14.11.2
1.14.11.2
1.14.11.2
1.14.11.2
1.14.11.2
1.14.11.2
5.3.4.1
1.14.11.2
1.14.11.2
1.14.11.2
5.3.4.1
Compound Iron Ascorbate Procollagen L-proline 2-Oxoglutarate O2 L-Proline Protein Cys-Cys Procollagen trans-4-hydroxy-L-proline Succinate CO2 Protein Cys-Cys
Type heavy metal carbohydrate,aromatic ring (with hetero atoms other than nitrogen atoms) peptide/protein carbohydrate,carboxyl group others amino acids peptide/protein,sulfhydryl group carbohydrate,peptide/protein carboxyl group others peptide/protein,sulfhydryl group
ChEBI 18248
82664
29073
30915
15379
26689
27140
17203
60039
15741
16526
PubChem 23925
54670067
51
977
145742
6971047
1110
21952380
280
1tjcA Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound
1tjcB Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound
1mekA Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound
1bjxA Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound
2bjxA Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound
1x5cA Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound

Reference for Active-site residues
resource references E.C.
Swiss-prot;P07237 & literature [28]

Active-site residues
PDB Catalytic residues Cofactor-binding residues Modified residues Main-chain involved in catalysis Comment
1tjcA Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain
1tjcB Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain
1mekA Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain CYS 36;GLY 37;HIS 38;CYS 39
1bjxA Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain
2bjxA Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain
1x5cA Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain CYS 37;GLY 38;HIS 39;CYS 40

References for Catalytic Mechanism
References Sections No. of steps in catalysis
[1]
p.25-26
[3]
p.3-6
[4]
p.332-333
[5]
p.16777-16779
[11]
Fig.3
[28]
Fig.8, p.291-293

References
[1]
Resource
Comments
Medline ID
PubMed ID 1961698
Journal Proteins
Year 1991
Volume 11
Pages 13-28
Authors Eklund H, Gleason FK, Holmgren A
Title Structural and functional relations among thioredoxins of different species.
Related PDB
Related UniProtKB
[2]
Resource
Comments
Medline ID
PubMed ID 1327760
Journal EMBO J
Year 1992
Volume 11
Pages 4213-7
Authors Vuori K, Pihlajaniemi T, Myllyla R, Kivirikko KI
Title Site-directed mutagenesis of human protein disulphide isomerase: effect on the assembly, activity and endoplasmic reticulum retention of human prolyl 4-hydroxylase in Spodoptera frugiperda insect cells.
Related PDB
Related UniProtKB
[3]
Resource
Comments
Medline ID
PubMed ID 7909462
Journal Protein Expr Purif
Year 1994
Volume 5
Pages 1-13
Authors Noiva R
Title Enzymatic catalysis of disulfide formation.
Related PDB
Related UniProtKB
[4]
Resource
Comments
Medline ID
PubMed ID 7940678
Journal Trends Biochem Sci
Year 1994
Volume 19
Pages 331-6
Authors Freedman RB, Hirst TR, Tuite MF
Title Protein disulphide isomerase: building bridges in protein folding.
Related PDB
Related UniProtKB
[5]
Resource
Comments
Medline ID
PubMed ID 8527452
Journal Biochemistry
Year 1995
Volume 34
Pages 16770-80
Authors Darby NJ, Creighton TE
Title Characterization of the active site cysteine residues of the thioredoxin-like domains of protein disulfide isomerase.
Related PDB
Related UniProtKB
[6]
Resource
Comments STRUCTURE BY NMR OF 18-137
Medline ID 96164391
PubMed ID 8580850
Journal Protein Sci
Year 1995
Volume 4
Pages 2587-93
Authors Kemmink J, Darby NJ, Dijkstra K, Scheek RM, Creighton TE
Title Nuclear magnetic resonance characterization of the N-terminal thioredoxin-like domain of protein disulfide isomerase.
Related PDB
Related UniProtKB P07237
[7]
Resource
Comments
Medline ID
PubMed ID 8615825
Journal Biochem J
Year 1996
Volume 315
Pages 533-6
Authors Lamberg A, Jauhiainen M, Metso J, Ehnholm C, Shoulders C, Scott J, Pihlajaniemi T, Kivirikko KI
Title The role of protein disulphide isomerase in the microsomal triacylglycerol transfer protein does not reside in its isomerase activity.
Related PDB
Related UniProtKB
[8]
Resource
Comments
Medline ID
PubMed ID 8756708
Journal Biochemistry
Year 1996
Volume 35
Pages 10517-28
Authors Darby NJ, Kemmink J, Creighton TE
Title Identifying and characterizing a structural domain of protein disulfide isomerase.
Related PDB
Related UniProtKB
[9]
Resource
Comments STRUCTURE BY NMR OF 18-137
Medline ID 96264879
PubMed ID 8672469
Journal Biochemistry
Year 1996
Volume 35
Pages 7684-91
Authors Kemmink J, Darby NJ, Dijkstra K, Nilges M, Creighton TE
Title Structure determination of the N-terminal thioredoxin-like domain of protein disulfide isomerase using multidimensional heteronuclear 13C/15N NMR spectroscopy.
Related PDB 1mek
Related UniProtKB P07237
[10]
Resource
Comments
Medline ID
PubMed ID 9094311
Journal Curr Biol
Year 1997
Volume 7
Pages 239-45
Authors Kemmink J, Darby NJ, Dijkstra K, Nilges M, Creighton TE
Title The folding catalyst protein disulfide isomerase is constructed of active and inactive thioredoxin modules.
Related PDB
Related UniProtKB
[11]
Resource
Comments
Medline ID
PubMed ID 9367991
Journal J Biol Chem
Year 1997
Volume 272
Pages 29399-402
Authors Gilbert HF
Title Protein disulfide isomerase and assisted protein folding.
Related PDB
Related UniProtKB
[12]
Resource
Comments
Medline ID
PubMed ID 9463371
Journal EMBO J
Year 1998
Volume 17
Pages 927-35
Authors Klappa P, Ruddock LW, Darby NJ, Freedman RB
Title The b' domain provides the principal peptide-binding site of protein disulfide isomerase but all domains contribute to binding of misfolded proteins.
Related PDB
Related UniProtKB
[13]
Resource
Comments
Medline ID
PubMed ID 9514721
Journal J Mol Biol
Year 1998
Volume 276
Pages 239-47
Authors Darby NJ, Penka E, Vincentelli R
Title The multi-domain structure of protein disulfide isomerase is essential for high catalytic efficiency.
Related PDB
Related UniProtKB
[14]
Resource
Comments
Medline ID
PubMed ID 9878051
Journal EMBO J
Year 1999
Volume 18
Pages 65-74
Authors Koivunen P, Pirneskoski A, Karvonen P, Ljung J, Helaakoski T, Notbohm H, Kivirikko KI
Title The acidic C-terminal domain of protein disulfide isomerase is not critical for the enzyme subunit function or for the chaperone or disulfide isomerase activities of the polypeptide.
Related PDB
Related UniProtKB
[15]
Resource
Comments
Medline ID
PubMed ID 10427749
Journal J Biomol NMR
Year 1999
Volume 14
Pages 195-6
Authors Dijkstra K, Karvonen P, Pirneskoski A, Koivunen P, Kivirikko KI, Darby NJ, van Straaten M, Scheek RM, Kemmink J
Title Assignment of 1H, 13C and 15N resonances of the a' domain of protein disulfide isomerase.
Related PDB
Related UniProtKB
[16]
Resource
Comments STRUCTURE BY NMR OF 136-245
Medline ID 99309858
PubMed ID 10383197
Journal J Biomol NMR
Year 1999
Volume 13
Pages 357-68
Authors Kemmink J, Dijkstra K, Mariani M, Scheek RM, Penka E, Nilges M, Darby NJ
Title The structure in solution of the b domain of protein disulfide isomerase.
Related PDB 1bjx 2bjx
Related UniProtKB P07237
[17]
Resource
Comments
Medline ID
PubMed ID 11134973
Journal J Biochem (Tokyo)
Year 2001
Volume 129
Pages 179-83
Authors Gao Y, Mehta K
Title Interchain disulfide bonds promote protein cross-linking during protein folding.
Related PDB
Related UniProtKB
[18]
Resource
Comments
Medline ID
PubMed ID 11375405
Journal J Biol Chem
Year 2001
Volume 276
Pages 27975-80
Authors Xiao R, Solovyov A, Gilbert HF, Holmgren A, Lundstrom-Ljung J
Title Combinations of protein-disulfide isomerase domains show that there is little correlation between isomerase activity and wild-type growth.
Related PDB
Related UniProtKB
[19]
Resource
Comments
Medline ID
PubMed ID 11839698
Journal EMBO Rep
Year 2002
Volume 3
Pages 136-40
Authors Freedman RB, Klappa P, Ruddock LW
Title Protein disulfide isomerases exploit synergy between catalytic and specific binding domains.
Related PDB
Related UniProtKB
[20]
Resource
Comments
Medline ID
PubMed ID 12384992
Journal J Cell Physiol
Year 2002
Volume 193
Pages 154-63
Authors Turano C, Coppari S, Altieri F, Ferraro A
Title Proteins of the PDI family: unpredicted non-ER locations and functions.
Related PDB
Related UniProtKB
[21]
Resource
Comments
Medline ID
PubMed ID 12766950
Journal Bioessays
Year 2003
Volume 25
Pages 603-11
Authors Clissold PM, Bicknell R
Title The thioredoxin-like fold: hidden domains in protein disulfide isomerases and other chaperone proteins.
Related PDB
Related UniProtKB
[22]
Resource
Comments
Medline ID
PubMed ID 12824157
Journal J Biol Chem
Year 2003
Volume 278
Pages 34966-74
Authors Hieta R, Kukkola L, Permi P, Pirila P, Kivirikko KI, Kilpelainen I, Myllyharju J
Title The peptide-substrate-binding domain of human collagen prolyl 4-hydroxylases. Backbone assignments, secondary structure, and binding of proline-rich peptides.
Related PDB
Related UniProtKB
[23]
Resource
Comments
Medline ID
PubMed ID 15137910
Journal Biochem J
Year 2004
Volume 382
Pages 169-76
Authors Kimura T, Nishida A, Ohara N, Yamagishi D, Horibe T, Kikuchi M
Title Functional analysis of the CXXC motif using phage antibodies that cross-react with protein disulphide-isomerase family proteins.
Related PDB
Related UniProtKB
[24]
Resource
Comments
Medline ID
PubMed ID 15147915
Journal FEBS Lett
Year 2004
Volume 566
Pages 311-5
Authors Horibe T, Iguchi D, Masuoka T, Gomi M, Kimura T, Kikuchi M
Title Replacement of domain b of human protein disulfide isomerase-related protein with domain b' of human protein disulfide isomerase dramatically increases its chaperone activity.
Related PDB
Related UniProtKB
[25]
Resource
Comments
Medline ID
PubMed ID 14985345
Journal J Biol Chem
Year 2004
Volume 279
Pages 18656-61
Authors Kukkola L, Koivunen P, Pakkanen O, Page AP, Myllyharju J
Title Collagen prolyl 4-hydroxylase tetramers and dimers show identical decreases in Km values for peptide substrates with increasing chain length: mutation of one of the two catalytic sites in the tetramer inactivates the enzyme by more than half.
Related PDB
Related UniProtKB
[26]
Resource
Comments
Medline ID
PubMed ID 14684740
Journal J Biol Chem
Year 2004
Volume 279
Pages 10374-81
Authors Pirneskoski A, Klappa P, Lobell M, Williamson RA, Byrne L, Alanen HI, Salo KE, Kivirikko KI, Freedman RB, Ruddock LW
Title Molecular characterization of the principal substrate binding site of the ubiquitous folding catalyst protein disulfide isomerase.
Related PDB
Related UniProtKB
[27]
Resource
Comments
Medline ID
PubMed ID 15323354
Journal J Biol Regul Homeost Agents
Year 2004
Volume 18
Pages 1-8
Authors Blasko B, Madi A, Fesus L
Title Structural elements responsible for transglutaminase activity of protein disulphide isomerases and thioredoxins.
Related PDB
Related UniProtKB
[28]
Resource
Comments
Medline ID
PubMed ID 14659757
Journal J Mol Biol
Year 2004
Volume 335
Pages 283-95
Authors Lappi AK, Lensink MF, Alanen HI, Salo KE, Lobell M, Juffer AH, Ruddock LW
Title A conserved arginine plays a role in the catalytic cycle of the protein disulphide isomerases.
Related PDB
Related UniProtKB
[29]
Resource
Comments
Medline ID
PubMed ID 15456751
Journal J Biol Chem
Year 2004
Volume 279
Pages 52255-61
Authors Pekkala M, Hieta R, Bergmann U, Kivirikko KI, Wierenga RK, Myllyharju J
Title The peptide-substrate-binding domain of collagen prolyl 4-hydroxylases is a tetratricopeptide repeat domain with functional aromatic residues.
Related PDB 1tjc
Related UniProtKB

Comments
This enzyme is compsed of two alpha subunits of Procollagen-proline dioxygenase (E.C. 1.14.11.2), and two beta subunits of PDI (E.C. 5.3.4.1).
The structure of the alpha subunit has been partially solved (PDB;1tjc). As for the beta subunits, it is composed of five domains, the N-terminal thioredoxin domain (PDB;1mek), the second and third domains, another thioredoxin domain (PDB;1x5c), and the C-terminal region. Although the structure of the third domain has not been solved yet, it must be similar to that of the second domain (see [10]).
The second and third domains have no catalytic activity, but they enhance the active sites on the first and fourth domains.
The enzyme, PDI, catalyzes rearrangement of disulfide bonds, according to the literature [11], [28], as follows.
(A) Electron transfer from the active site to the disulfide bond of substrate, releasing an intermediate with a pair of reduced cysteine residues.
(B) Electron transfer from the active site to the other disulfide bond of substrate, releasing an intermediate with another pair of reduced cysteine residues.
(C) Electron transfer from a pair of reduced cysteine residues to the disulfide bond at the active site.
(D) Electron transfer from another pair of reduced cysteine residues to the disulfide bond at the active site.

Created Updated
2005-05-31 2009-02-26