EzCatDB: M00184

DB codeM00184
CATH domainDomain 1-.-.-.-
Domain 21.25.40.10
Domain 3-.-.-.-
Domain 42.60.-.-
Domain 53.40.30.10Catalytic domain
Domain 63.40.30.10
Domain 73.40.30.10
Domain 83.40.30.10Catalytic domain
Domain 9-.-.-.-
E.C.1.14.11.2,5.3.4.1
CSA1mek
MACiEM0191

CATH domainRelated DB codes (homologues)
1.25.40.10D00469
3.40.30.10S00916,S00279,D00866,D00869,D00870,D00278

Enzyme Name
Swiss-protKEGG

P13674P07237
Protein nameProlyl 4-hydroxylase subunit alpha-1Protein disulfide-isomeraseprocollagen-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)

SynonymsEC 1.14.11.2
4-PH alpha-1
Procollagen-proline,2-oxoglutarate-4-dioxygenase subunit alpha-1
PDI
EC 5.3.4.1
Prolyl 4-hydroxylase subunit beta
Cellular thyroid hormone-binding protein
p55

KEGG pathways
MAP codePathwaysE.C.
MAP00330Arginine and proline metabolism1.14.11.2

Swiss-prot:Accession NumberP13674P07237
Entry nameP4HA1_HUMANPDIA1_HUMAN
ActivityProcollagen L-proline + 2-oxoglutarate + O(2) = procollagen trans-4-hydroxy-L-proline + succinate + CO(2).Catalyzes the rearrangement of -S-S- bonds in proteins.
SubunitHeterotetramer of two alpha-1 chains and two beta chains (the beta chain is the multi-functional PDI).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.
Subcellular locationEndoplasmic reticulum lumen.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.
CofactorBinds 1 Fe(2+) ion per subunit.,Ascorbate.


CofactorsSubstratesProducts
KEGG-idC00023C00072C01078C00026C00007C00148C02461C04398C00042C00011C02461
E.C.1.14.11.21.14.11.21.14.11.21.14.11.21.14.11.21.14.11.25.3.4.11.14.11.21.14.11.21.14.11.25.3.4.1
CompoundIronAscorbateProcollagen L-proline2-OxoglutarateO2L-ProlineProtein Cys-CysProcollagen trans-4-hydroxy-L-prolineSuccinateCO2Protein Cys-Cys
Typeheavy metalcarbohydrate,aromatic ring (with hetero atoms other than nitrogen atoms)peptide/proteincarbohydrate,carboxyl groupothersamino acidspeptide/protein,sulfhydryl groupcarbohydrate,peptide/proteincarboxyl groupotherspeptide/protein,sulfhydryl group
1tjcAUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnbound
1tjcBUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnbound
1mekAUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnbound
1bjxAUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnbound
2bjxAUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnbound
1x5cAUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnbound

Active-site residues
resource
Swiss-prot;P07237 & literature [28]
pdbCatalytic residues
1tjcA
1tjcB
1mekACYS 36;GLY 37;HIS 38;CYS 39
1bjxA
2bjxA
1x5cACYS 37;GLY 38;HIS 39;CYS 40

References for Catalytic Mechanism
ReferencesSectionsNo. 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]
PubMed ID1961698
JournalProteins
Year1991
Volume11
Pages13-28
AuthorsEklund H, Gleason FK, Holmgren A
TitleStructural and functional relations among thioredoxins of different species.
[2]
PubMed ID1327760
JournalEMBO J
Year1992
Volume11
Pages4213-7
AuthorsVuori K, Pihlajaniemi T, Myllyla R, Kivirikko KI
TitleSite-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.
[3]
PubMed ID7909462
JournalProtein Expr Purif
Year1994
Volume5
Pages1-13
AuthorsNoiva R
TitleEnzymatic catalysis of disulfide formation.
[4]
PubMed ID7940678
JournalTrends Biochem Sci
Year1994
Volume19
Pages331-6
AuthorsFreedman RB, Hirst TR, Tuite MF
TitleProtein disulphide isomerase: building bridges in protein folding.
[5]
PubMed ID8527452
JournalBiochemistry
Year1995
Volume34
Pages16770-80
AuthorsDarby NJ, Creighton TE
TitleCharacterization of the active site cysteine residues of the thioredoxin-like domains of protein disulfide isomerase.
[6]
CommentsSTRUCTURE BY NMR OF 18-137
Medline ID96164391
PubMed ID8580850
JournalProtein Sci
Year1995
Volume4
Pages2587-93
AuthorsKemmink J, Darby NJ, Dijkstra K, Scheek RM, Creighton TE
TitleNuclear magnetic resonance characterization of the N-terminal thioredoxin-like domain of protein disulfide isomerase.
Related Swiss-protP07237
[7]
PubMed ID8615825
JournalBiochem J
Year1996
Volume315
Pages533-6
AuthorsLamberg A, Jauhiainen M, Metso J, Ehnholm C, Shoulders C, Scott J, Pihlajaniemi T, Kivirikko KI
TitleThe role of protein disulphide isomerase in the microsomal triacylglycerol transfer protein does not reside in its isomerase activity.
[8]
PubMed ID8756708
JournalBiochemistry
Year1996
Volume35
Pages10517-28
AuthorsDarby NJ, Kemmink J, Creighton TE
TitleIdentifying and characterizing a structural domain of protein disulfide isomerase.
[9]
CommentsSTRUCTURE BY NMR OF 18-137
Medline ID96264879
PubMed ID8672469
JournalBiochemistry
Year1996
Volume35
Pages7684-91
AuthorsKemmink J, Darby NJ, Dijkstra K, Nilges M, Creighton TE
TitleStructure determination of the N-terminal thioredoxin-like domain of protein disulfide isomerase using multidimensional heteronuclear 13C/15N NMR spectroscopy.
Related PDB1mek
Related Swiss-protP07237
[10]
PubMed ID9094311
JournalCurr Biol
Year1997
Volume7
Pages239-45
AuthorsKemmink J, Darby NJ, Dijkstra K, Nilges M, Creighton TE
TitleThe folding catalyst protein disulfide isomerase is constructed of active and inactive thioredoxin modules.
[11]
PubMed ID9367991
JournalJ Biol Chem
Year1997
Volume272
Pages29399-402
AuthorsGilbert HF
TitleProtein disulfide isomerase and assisted protein folding.
[12]
PubMed ID9463371
JournalEMBO J
Year1998
Volume17
Pages927-35
AuthorsKlappa P, Ruddock LW, Darby NJ, Freedman RB
TitleThe b' domain provides the principal peptide-binding site of protein disulfide isomerase but all domains contribute to binding of misfolded proteins.
[13]
PubMed ID9514721
JournalJ Mol Biol
Year1998
Volume276
Pages239-47
AuthorsDarby NJ, Penka E, Vincentelli R
TitleThe multi-domain structure of protein disulfide isomerase is essential for high catalytic efficiency.
[14]
PubMed ID9878051
JournalEMBO J
Year1999
Volume18
Pages65-74
AuthorsKoivunen P, Pirneskoski A, Karvonen P, Ljung J, Helaakoski T, Notbohm H, Kivirikko KI
TitleThe 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.
[15]
PubMed ID10427749
JournalJ Biomol NMR
Year1999
Volume14
Pages195-6
AuthorsDijkstra K, Karvonen P, Pirneskoski A, Koivunen P, Kivirikko KI, Darby NJ, van Straaten M, Scheek RM, Kemmink J
TitleAssignment of 1H, 13C and 15N resonances of the a' domain of protein disulfide isomerase.
[16]
CommentsSTRUCTURE BY NMR OF 136-245
Medline ID99309858
PubMed ID10383197
JournalJ Biomol NMR
Year1999
Volume13
Pages357-68
AuthorsKemmink J, Dijkstra K, Mariani M, Scheek RM, Penka E, Nilges M, Darby NJ
TitleThe structure in solution of the b domain of protein disulfide isomerase.
Related PDB1bjx,2bjx
Related Swiss-protP07237
[17]
PubMed ID11134973
JournalJ Biochem (Tokyo)
Year2001
Volume129
Pages179-83
AuthorsGao Y, Mehta K
TitleInterchain disulfide bonds promote protein cross-linking during protein folding.
[18]
PubMed ID11375405
JournalJ Biol Chem
Year2001
Volume276
Pages27975-80
AuthorsXiao R, Solovyov A, Gilbert HF, Holmgren A, Lundstrom-Ljung J
TitleCombinations of protein-disulfide isomerase domains show that there is little correlation between isomerase activity and wild-type growth.
[19]
PubMed ID11839698
JournalEMBO Rep
Year2002
Volume3
Pages136-40
AuthorsFreedman RB, Klappa P, Ruddock LW
TitleProtein disulfide isomerases exploit synergy between catalytic and specific binding domains.
[20]
PubMed ID12384992
JournalJ Cell Physiol
Year2002
Volume193
Pages154-63
AuthorsTurano C, Coppari S, Altieri F, Ferraro A
TitleProteins of the PDI family: unpredicted non-ER locations and functions.
[21]
PubMed ID12766950
JournalBioessays
Year2003
Volume25
Pages603-11
AuthorsClissold PM, Bicknell R
TitleThe thioredoxin-like fold: hidden domains in protein disulfide isomerases and other chaperone proteins.
[22]
PubMed ID12824157
JournalJ Biol Chem
Year2003
Volume278
Pages34966-74
AuthorsHieta R, Kukkola L, Permi P, Pirila P, Kivirikko KI, Kilpelainen I, Myllyharju J
TitleThe peptide-substrate-binding domain of human collagen prolyl 4-hydroxylases. Backbone assignments, secondary structure, and binding of proline-rich peptides.
[23]
PubMed ID15137910
JournalBiochem J
Year2004
Volume382
Pages169-76
AuthorsKimura T, Nishida A, Ohara N, Yamagishi D, Horibe T, Kikuchi M
TitleFunctional analysis of the CXXC motif using phage antibodies that cross-react with protein disulphide-isomerase family proteins.
[24]
PubMed ID15147915
JournalFEBS Lett
Year2004
Volume566
Pages311-5
AuthorsHoribe T, Iguchi D, Masuoka T, Gomi M, Kimura T, Kikuchi M
TitleReplacement of domain b of human protein disulfide isomerase-related protein with domain b' of human protein disulfide isomerase dramatically increases its chaperone activity.
[25]
PubMed ID14985345
JournalJ Biol Chem
Year2004
Volume279
Pages18656-61
AuthorsKukkola L, Koivunen P, Pakkanen O, Page AP, Myllyharju J
TitleCollagen 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.
[26]
PubMed ID14684740
JournalJ Biol Chem
Year2004
Volume279
Pages10374-81
AuthorsPirneskoski A, Klappa P, Lobell M, Williamson RA, Byrne L, Alanen HI, Salo KE, Kivirikko KI, Freedman RB, Ruddock LW
TitleMolecular characterization of the principal substrate binding site of the ubiquitous folding catalyst protein disulfide isomerase.
[27]
PubMed ID15323354
JournalJ Biol Regul Homeost Agents
Year2004
Volume18
Pages1-8
AuthorsBlasko B, Madi A, Fesus L
TitleStructural elements responsible for transglutaminase activity of protein disulphide isomerases and thioredoxins.
[28]
PubMed ID14659757
JournalJ Mol Biol
Year2004
Volume335
Pages283-95
AuthorsLappi AK, Lensink MF, Alanen HI, Salo KE, Lobell M, Juffer AH, Ruddock LW
TitleA conserved arginine plays a role in the catalytic cycle of the protein disulphide isomerases.
[29]
PubMed ID15456751
JournalJ Biol Chem
Year2004
Volume279
Pages52255-61
AuthorsPekkala M, Hieta R, Bergmann U, Kivirikko KI, Wierenga RK, Myllyharju J
TitleThe peptide-substrate-binding domain of collagen prolyl 4-hydroxylases is a tetratricopeptide repeat domain with functional aromatic residues.
Related PDB1tjc

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.

createdupdated
2005-05-312009-02-26


Copyright: Nozomi Nagano, JST & CBRC-AIST
Funded by PRESTO/Japan Science and Technology Corporation (JST) (December 2001 - November 2004)
Funded by Grant-in-Aid for Publication of Scientific Research Results/Japan Society for the Promotion of Science (JSPS) (April 2005 - March 2006)
Funded by Grant-in-Aid for Scientific Research (B)/Japan Society for the Promotion of Science (JSPS) (April 2005 - March 2008)
Funded by BIRD/Japan Science and Technology Corporation (JST) (September 2005 - September 2010)
Funded by BIRD/Japan Science and Technology Corporation (JST) (October 2007 - September 2010)
Funded by Grant-in-Aid for Publication of Scientific Research Results/Japan Society for the Promotion of Science (JSPS) (April 2011 - March 2012)

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