Full text data of P4HB
P4HB
(ERBA2L, PDI, PDIA1, PO4DB)
[Confidence: high (present in two of the MS resources)]
Protein disulfide-isomerase; PDI; 5.3.4.1 (Cellular thyroid hormone-binding protein; Prolyl 4-hydroxylase subunit beta; p55; Flags: Precursor)
Protein disulfide-isomerase; PDI; 5.3.4.1 (Cellular thyroid hormone-binding protein; Prolyl 4-hydroxylase subunit beta; p55; Flags: Precursor)
hRBCD
IPI00010796
IPI00010796 Protein disulfide-isomerase precursor Protein disulfide-isomerase precursor membrane n/a 3 n/a n/a 1 n/a n/a n/a 3 n/a n/a n/a n/a n/a n/a n/a n/a 1 6 1 ER lumen, extracellular region n/a found at its expected molecular weight found at molecular weight
IPI00010796 Protein disulfide-isomerase precursor Protein disulfide-isomerase precursor membrane n/a 3 n/a n/a 1 n/a n/a n/a 3 n/a n/a n/a n/a n/a n/a n/a n/a 1 6 1 ER lumen, extracellular region n/a found at its expected molecular weight found at molecular weight
UniProt
P07237
ID PDIA1_HUMAN Reviewed; 508 AA.
AC P07237; B2RDQ2; P30037; P32079; Q15205; Q6LDE5;
DT 01-APR-1988, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-NOV-1997, sequence version 3.
DT 22-JAN-2014, entry version 187.
DE RecName: Full=Protein disulfide-isomerase;
DE Short=PDI;
DE EC=5.3.4.1;
DE AltName: Full=Cellular thyroid hormone-binding protein;
DE AltName: Full=Prolyl 4-hydroxylase subunit beta;
DE AltName: Full=p55;
DE Flags: Precursor;
GN Name=P4HB; Synonyms=ERBA2L, PDI, PDIA1, PO4DB;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=3034602;
RA Pihlajaniemi T., Helaakoski T., Tasanen K., Myllylae R.,
RA Huhtala M.-L., Koivu J., Kivirikko K.I.;
RT "Molecular cloning of the beta-subunit of human prolyl 4-hydroxylase.
RT This subunit and protein disulphide isomerase are products of the same
RT gene.";
RL EMBO J. 6:643-649(1987).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=3611107;
RA Cheng S.-Y., Gong Q.-H., Parkison C., Robinson E.A., Appella E.,
RA Merlino G.T., Pastan I.;
RT "The nucleotide sequence of a human cellular thyroid hormone binding
RT protein present in endoplasmic reticulum.";
RL J. Biol. Chem. 262:11221-11227(1987).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC TISSUE=Blood;
RX PubMed=2846539;
RA Tasanen K., Parkkonen T., Chow L.T., Kivirikko K.I., Pihlajaniemi T.;
RT "Characterization of the human gene for a polypeptide that acts both
RT as the beta subunit of prolyl 4-hydroxylase and as protein disulfide
RT isomerase.";
RL J. Biol. Chem. 263:16218-16224(1988).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Synovium;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Colon, Lung, and Skin;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [7]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-24.
RX PubMed=1597478;
RA Tasanen K., Oikarinen J., Kivirikko K.I., Pihlajaniemi T.;
RT "Promoter of the gene for the multifunctional protein disulfide
RT isomerase polypeptide. Functional significance of the six CCAAT boxes
RT and other promoter elements.";
RL J. Biol. Chem. 267:11513-11519(1992).
RN [8]
RP PROTEIN SEQUENCE OF 18-41.
RC TISSUE=Colon carcinoma;
RX PubMed=9150948; DOI=10.1002/elps.1150180344;
RA Ji H., Reid G.E., Moritz R.L., Eddes J.S., Burgess A.W., Simpson R.J.;
RT "A two-dimensional gel database of human colon carcinoma proteins.";
RL Electrophoresis 18:605-613(1997).
RN [9]
RP PROTEIN SEQUENCE OF 18-30.
RC TISSUE=Platelet;
RX PubMed=12665801; DOI=10.1038/nbt810;
RA Gevaert K., Goethals M., Martens L., Van Damme J., Staes A.,
RA Thomas G.R., Vandekerckhove J.;
RT "Exploring proteomes and analyzing protein processing by mass
RT spectrometric identification of sorted N-terminal peptides.";
RL Nat. Biotechnol. 21:566-569(2003).
RN [10]
RP PROTEIN SEQUENCE OF 18-29.
RC TISSUE=Liver;
RA Frutiger S., Hughes G.J.;
RL Submitted (FEB-1996) to UniProtKB.
RN [11]
RP PROTEIN SEQUENCE OF 18-26.
RX PubMed=2079031; DOI=10.1002/elps.1150111019;
RA Ward L.D., Hong J., Whitehead R.H., Simpson R.J.;
RT "Development of a database of amino acid sequences for human colon
RT carcinoma proteins separated by two-dimensional polyacrylamide gel
RT electrophoresis.";
RL Electrophoresis 11:883-891(1990).
RN [12]
RP PRELIMINARY PROTEIN SEQUENCE OF 19-28.
RC TISSUE=Liver;
RX PubMed=1286669; DOI=10.1002/elps.11501301201;
RA Hochstrasser D.F., Frutiger S., Paquet N., Bairoch A., Ravier F.,
RA Pasquali C., Sanchez J.-C., Tissot J.-D., Bjellqvist B., Vargas R.,
RA Appel R.D., Hughes G.J.;
RT "Human liver protein map: a reference database established by
RT microsequencing and gel comparison.";
RL Electrophoresis 13:992-1001(1992).
RN [13]
RP PROTEIN SEQUENCE OF 19-28.
RX PubMed=9399589;
RA Urade R., Oda T., Ito H., Moriyama T., Utsumi S., Kito M.;
RT "Functions of characteristic Cys-Gly-His-Cys (CGHC) and Gln-Glu-Asp-
RT Leu (QEDL) motifs of microsomal ER-60 protease.";
RL J. Biochem. 122:834-842(1997).
RN [14]
RP PROTEIN SEQUENCE OF 201-207; 223-230; 286-308 AND 402-409, AND MASS
RP SPECTROMETRY.
RC TISSUE=Brain, Cajal-Retzius cell, and Fetal brain cortex;
RA Lubec G., Vishwanath V., Chen W.-Q., Sun Y.;
RL Submitted (DEC-2008) to UniProtKB.
RN [15]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 293-508.
RX PubMed=3342239; DOI=10.1016/0167-4781(88)90080-2;
RA Morris J.I., Varandani P.T.;
RT "Characterization of a cDNA for human glutathione-insulin
RT transhydrogenase (protein-disulfide isomerase/oxidoreductase).";
RL Biochim. Biophys. Acta 949:169-180(1988).
RN [16]
RP PROTEIN SEQUENCE OF 317-325; 350-369 AND 401-419.
RX PubMed=1699755; DOI=10.1002/elps.1150110703;
RA Bauw G., Rasmussen H.H., van den Bulcke M., van Damme J., Puype M.,
RA Gesser B., Celis J.E., Vandekerckhove J.;
RT "Two-dimensional gel electrophoresis, protein electroblotting and
RT microsequencing: a direct link between proteins and genes.";
RL Electrophoresis 11:528-536(1990).
RN [17]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=10636893; DOI=10.1074/jbc.275.3.1920;
RA Mezghrani A., Courageot J., Mani J.-C., Pugniere M., Bastiani P.,
RA Miquelis R.;
RT "Protein-disulfide isomerase (PDI) in FRTL5 cells. pH-dependent
RT thyroglobulin/PDI interactions determine a novel PDI function in the
RT post-endoplasmic reticulum of thyrocytes.";
RL J. Biol. Chem. 275:1920-1929(2000).
RN [18]
RP REDUCTION OF HIV-1 SURFACE PROTEIN GP120 DISULFIDE BONDS, AND
RP SUBCELLULAR LOCATION.
RX PubMed=11181151; DOI=10.1086/318823;
RA Fenouillet E., Barbouche R., Courageot J., Miquelis R.;
RT "The catalytic activity of protein disulfide isomerase is involved in
RT human immunodeficiency virus envelope-mediated membrane fusion after
RT CD4 cell binding.";
RL J. Infect. Dis. 183:744-752(2001).
RN [19]
RP FUNCTION.
RX PubMed=12485997; DOI=10.1093/emboj/cdf685;
RA Lumb R.A., Bulleid N.J.;
RT "Is protein disulfide isomerase a redox-dependent molecular
RT chaperone?";
RL EMBO J. 21:6763-6770(2002).
RN [20]
RP INTERACTION WITH UBQLN1.
RX PubMed=12095988; DOI=10.1074/jbc.M203412200;
RA Ko H.S., Uehara T., Nomura Y.;
RT "Role of ubiquilin associated with protein-disulfide isomerase in the
RT endoplasmic reticulum in stress-induced apoptotic cell death.";
RL J. Biol. Chem. 277:35386-35392(2002).
RN [21]
RP REDUCTION OF HIV-1 SURFACE PROTEIN GP120 DISULFIDE BONDS.
RX PubMed=12218051; DOI=10.1074/jbc.M204547200;
RA Gallina A., Hanley T.M., Mandel R., Trahey M., Broder C.C.,
RA Viglianti G.A., Ryser H.J.;
RT "Inhibitors of protein-disulfide isomerase prevent cleavage of
RT disulfide bonds in receptor-bound glycoprotein 120 and prevent HIV-1
RT entry.";
RL J. Biol. Chem. 277:50579-50588(2002).
RN [22]
RP REDUCTION OF HIV-1 SURFACE PROTEIN GP120 DISULFIDE BONDS.
RX PubMed=12218052; DOI=10.1074/jbc.M205467200;
RA Barbouche R., Miquelis R., Jones I.M., Fenouillet E.;
RT "Protein-disulfide isomerase-mediated reduction of two disulfide bonds
RT of HIV envelope glycoprotein 120 occurs post-CXCR4 binding and is
RT required for fusion.";
RL J. Biol. Chem. 278:3131-3136(2003).
RN [23]
RP SUBCELLULAR LOCATION [LARGE SCALE ANALYSIS], AND MASS SPECTROMETRY.
RC TISSUE=Melanoma;
RX PubMed=12643545; DOI=10.1021/pr025562r;
RA Basrur V., Yang F., Kushimoto T., Higashimoto Y., Yasumoto K.,
RA Valencia J., Muller J., Vieira W.D., Watabe H., Shabanowitz J.,
RA Hearing V.J., Hunt D.F., Appella E.;
RT "Proteomic analysis of early melanosomes: identification of novel
RT melanosomal proteins.";
RL J. Proteome Res. 2:69-79(2003).
RN [24]
RP REVIEW.
RX PubMed=15158710; DOI=10.1016/j.bbapap.2004.02.017;
RA Wilkinson B., Gilbert H.F.;
RT "Protein disulfide isomerase.";
RL Biochim. Biophys. Acta 1699:35-44(2004).
RN [25]
RP REDUCTION OF HIV-1 SURFACE PROTEIN GP120 DISULFIDE BONDS.
RX PubMed=14592831; DOI=10.1182/blood-2003-05-1390;
RA Markovic I., Stantchev T.S., Fields K.H., Tiffany L.J., Tomic M.,
RA Weiss C.D., Broder C.C., Strebel K., Clouse K.A.;
RT "Thiol/disulfide exchange is a prerequisite for CXCR4-tropic HIV-1
RT envelope-mediated T-cell fusion during viral entry.";
RL Blood 103:1586-1594(2004).
RN [26]
RP REDUCTION OF HIV-1 SURFACE PROTEIN GP120 DISULFIDE BONDS.
RX PubMed=15644496; DOI=10.1124/mol.104.008276;
RA Barbouche R., Lortat-Jacob H., Jones I.M., Fenouillet E.;
RT "Glycosaminoglycans and protein disulfide isomerase-mediated reduction
RT of HIV Env.";
RL Mol. Pharmacol. 67:1111-1118(2005).
RN [27]
RP SUBCELLULAR LOCATION [LARGE SCALE ANALYSIS], AND MASS SPECTROMETRY.
RC TISSUE=Melanoma;
RX PubMed=17081065; DOI=10.1021/pr060363j;
RA Chi A., Valencia J.C., Hu Z.-Z., Watabe H., Yamaguchi H.,
RA Mangini N.J., Huang H., Canfield V.A., Cheng K.C., Yang F., Abe R.,
RA Yamagishi S., Shabanowitz J., Hearing V.J., Wu C., Appella E.,
RA Hunt D.F.;
RT "Proteomic and bioinformatic characterization of the biogenesis and
RT function of melanosomes.";
RL J. Proteome Res. 5:3135-3144(2006).
RN [28]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [29]
RP STRUCTURE BY NMR OF 18-137.
RX PubMed=8580850;
RA Kemmink J., Darby N.J., Dijkstra K., Scheek R.M., Creighton T.E.;
RT "Nuclear magnetic resonance characterization of the N-terminal
RT thioredoxin-like domain of protein disulfide isomerase.";
RL Protein Sci. 4:2587-2593(1995).
RN [30]
RP STRUCTURE BY NMR OF 18-137, AND DISULFIDE BOND.
RX PubMed=8672469; DOI=10.1021/bi960335m;
RA Kemmink J., Darby N.J., Dijkstra K., Nilges M., Creighton T.E.;
RT "Structure determination of the N-terminal thioredoxin-like domain of
RT protein disulfide isomerase using multidimensional heteronuclear
RT 13C/15N NMR spectroscopy.";
RL Biochemistry 35:7684-7691(1996).
RN [31]
RP STRUCTURE BY NMR OF 136-245.
RX PubMed=10383197; DOI=10.1023/A:1008341820489;
RA Kemmink J., Dijkstra K., Mariani M., Scheek R.M., Penka E., Nilges M.,
RA Darby N.J.;
RT "The structure in solution of the B domain of protein disulfide
RT isomerase.";
RL J. Biomol. NMR 13:357-368(1999).
RN [32]
RP STRUCTURE BY NMR OF 368-477.
RG RIKEN structural genomics initiative (RSGI);
RT "The solution structure of the second thioredoxin-like domain of human
RT protein disulfide-isomerase.";
RL Submitted (NOV-2005) to the PDB data bank.
CC -!- FUNCTION: This multifunctional protein catalyzes the formation,
CC breakage and rearrangement of disulfide bonds. At the cell
CC surface, seems to act as a reductase that cleaves disulfide bonds
CC of proteins attached to the cell. May therefore cause structural
CC modifications of exofacial proteins. Inside the cell, seems to
CC form/rearrange disulfide bonds of nascent proteins. At high
CC concentrations, functions as a chaperone that inhibits aggregation
CC of misfolded proteins. At low concentrations, facilitates
CC aggregation (anti-chaperone activity). May be involved with other
CC chaperones in the structural modification of the TG precursor in
CC hormone biogenesis. Also acts a structural subunit of various
CC enzymes such as prolyl 4-hydroxylase and microsomal
CC triacylglycerol transfer protein MTTP.
CC -!- CATALYTIC ACTIVITY: Catalyzes the rearrangement of -S-S- bonds in
CC proteins.
CC -!- SUBUNIT: Homodimer. Monomers and homotetramers may also occur.
CC Also constitutes the structural subunit of prolyl 4-hydroxylase
CC and of the microsomal triacylglycerol transfer protein MTTP in
CC mammalian cells. Stabilizes both enzymes and retain them in the ER
CC without contributing to the catalytic activity (By similarity).
CC Binds UBQLN1. Binds to CD4, and upon HIV-1 binding to the cell
CC membrane, is part of a P4HB/PDI-CD4-CXCR4-gp120 complex.
CC -!- INTERACTION:
CC Q96HE7:ERO1L; NbExp=2; IntAct=EBI-395883, EBI-2564539;
CC Q8TCT9:HM13; NbExp=3; IntAct=EBI-395883, EBI-347472;
CC Q13162:PRDX4; NbExp=2; IntAct=EBI-395883, EBI-2211957;
CC Q03518:TAP1; NbExp=4; IntAct=EBI-395883, EBI-747259;
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum lumen. Melanosome.
CC Cell membrane; Peripheral membrane protein (Potential).
CC Note=Highly abundant. In some cell types, seems to be also
CC secreted or associated with the plasma membrane, where it
CC undergoes constant shedding and replacement from intracellular
CC sources (Probable). Localizes near CD4-enriched regions on
CC lymphoid cell surfaces. Identified by mass spectrometry in
CC melanosome fractions from stage I to stage IV.
CC -!- MISCELLANEOUS: Reduces and may activate fusogenic properties of
CC HIV-1 gp120 surface protein, thereby enabling HIV-1 entry into the
CC cell.
CC -!- SIMILARITY: Belongs to the protein disulfide isomerase family.
CC -!- SIMILARITY: Contains 2 thioredoxin domains.
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DR EMBL; X05130; CAA28775.1; -; mRNA.
DR EMBL; J02783; AAA61169.1; -; mRNA.
DR EMBL; M22806; AAC13652.1; -; Genomic_DNA.
DR EMBL; M22803; AAC13652.1; JOINED; Genomic_DNA.
DR EMBL; M22804; AAC13652.1; JOINED; Genomic_DNA.
DR EMBL; M22805; AAC13652.1; JOINED; Genomic_DNA.
DR EMBL; AK315631; BAG37999.1; -; mRNA.
DR EMBL; CH471099; EAW89690.1; -; Genomic_DNA.
DR EMBL; BC010859; AAH10859.1; -; mRNA.
DR EMBL; BC029617; AAH29617.1; -; mRNA.
DR EMBL; BC071892; AAH71892.1; -; mRNA.
DR EMBL; S37207; AAB22262.2; -; Genomic_DNA.
DR EMBL; X07077; CAA30112.1; -; mRNA.
DR PIR; A31913; ISHUSS.
DR RefSeq; NP_000909.2; NM_000918.3.
DR UniGene; Hs.464336; -.
DR PDB; 1BJX; NMR; -; A=136-245.
DR PDB; 1MEK; NMR; -; A=18-137.
DR PDB; 1X5C; NMR; -; A=368-475.
DR PDB; 2BJX; NMR; -; A=136-245.
DR PDB; 2K18; NMR; -; A=135-357.
DR PDB; 3BJ5; X-ray; 2.20 A; A=230-368.
DR PDB; 3UEM; X-ray; 2.29 A; A=137-479.
DR PDB; 4EKZ; X-ray; 2.51 A; A=18-479.
DR PDB; 4EL1; X-ray; 2.88 A; A/B=18-479.
DR PDBsum; 1BJX; -.
DR PDBsum; 1MEK; -.
DR PDBsum; 1X5C; -.
DR PDBsum; 2BJX; -.
DR PDBsum; 2K18; -.
DR PDBsum; 3BJ5; -.
DR PDBsum; 3UEM; -.
DR PDBsum; 4EKZ; -.
DR PDBsum; 4EL1; -.
DR ProteinModelPortal; P07237; -.
DR SMR; P07237; 17-478.
DR IntAct; P07237; 29.
DR MINT; MINT-4999403; -.
DR STRING; 9606.ENSP00000327801; -.
DR BindingDB; P07237; -.
DR ChEMBL; CHEMBL2364681; -.
DR PhosphoSite; P07237; -.
DR DMDM; 2507460; -.
DR DOSAC-COBS-2DPAGE; P07237; -.
DR OGP; P07237; -.
DR REPRODUCTION-2DPAGE; IPI00010796; -.
DR REPRODUCTION-2DPAGE; P07237; -.
DR SWISS-2DPAGE; P07237; -.
DR PaxDb; P07237; -.
DR PeptideAtlas; P07237; -.
DR PRIDE; P07237; -.
DR DNASU; 5034; -.
DR Ensembl; ENST00000331483; ENSP00000327801; ENSG00000185624.
DR GeneID; 5034; -.
DR KEGG; hsa:5034; -.
DR UCSC; uc002kbn.1; human.
DR CTD; 5034; -.
DR GeneCards; GC17M079801; -.
DR HGNC; HGNC:8548; P4HB.
DR HPA; CAB012463; -.
DR HPA; HPA018884; -.
DR MIM; 176790; gene.
DR neXtProt; NX_P07237; -.
DR PharmGKB; PA32876; -.
DR eggNOG; COG0526; -.
DR HOGENOM; HOG000162459; -.
DR HOVERGEN; HBG005920; -.
DR InParanoid; P07237; -.
DR KO; K09580; -.
DR OMA; KSHILMF; -.
DR OrthoDB; EOG7VHSX1; -.
DR PhylomeDB; P07237; -.
DR BRENDA; 5.3.4.1; 2681.
DR Reactome; REACT_111217; Metabolism.
DR Reactome; REACT_118779; Extracellular matrix organization.
DR ChiTaRS; P4HB; human.
DR EvolutionaryTrace; P07237; -.
DR GeneWiki; P4HB; -.
DR GenomeRNAi; 5034; -.
DR NextBio; 19398; -.
DR PMAP-CutDB; P07237; -.
DR PRO; PR:P07237; -.
DR ArrayExpress; P07237; -.
DR Bgee; P07237; -.
DR CleanEx; HS_P4HB; -.
DR Genevestigator; P07237; -.
DR GO; GO:0009986; C:cell surface; IDA:UniProtKB.
DR GO; GO:0005788; C:endoplasmic reticulum lumen; TAS:Reactome.
DR GO; GO:0005793; C:endoplasmic reticulum-Golgi intermediate compartment; IDA:UniProtKB.
DR GO; GO:0005576; C:extracellular region; NAS:UniProtKB.
DR GO; GO:0042470; C:melanosome; IEA:UniProtKB-SubCell.
DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0004656; F:procollagen-proline 4-dioxygenase activity; IDA:MGI.
DR GO; GO:0003756; F:protein disulfide isomerase activity; TAS:ProtInc.
DR GO; GO:0015035; F:protein disulfide oxidoreductase activity; IEA:InterPro.
DR GO; GO:0045454; P:cell redox homeostasis; IEA:InterPro.
DR GO; GO:0071456; P:cellular response to hypoxia; IMP:BHF-UCL.
DR GO; GO:0030198; P:extracellular matrix organization; TAS:Reactome.
DR GO; GO:0006662; P:glycerol ether metabolic process; IEA:InterPro.
DR GO; GO:0042157; P:lipoprotein metabolic process; TAS:Reactome.
DR GO; GO:0018401; P:peptidyl-proline hydroxylation to 4-hydroxy-L-proline; IDA:MGI.
DR GO; GO:1902175; P:regulation of intrinsic apoptotic signaling pathway in response to oxidative stress; IMP:BHF-UCL.
DR GO; GO:0034976; P:response to endoplasmic reticulum stress; IMP:BHF-UCL.
DR Gene3D; 3.40.30.10; -; 4.
DR InterPro; IPR005788; Disulphide_isomerase.
DR InterPro; IPR005792; Prot_disulphide_isomerase.
DR InterPro; IPR005746; Thioredoxin.
DR InterPro; IPR012336; Thioredoxin-like_fold.
DR InterPro; IPR017937; Thioredoxin_CS.
DR InterPro; IPR013766; Thioredoxin_domain.
DR Pfam; PF00085; Thioredoxin; 2.
DR PRINTS; PR00421; THIOREDOXIN.
DR SUPFAM; SSF52833; SSF52833; 4.
DR TIGRFAMs; TIGR01130; ER_PDI_fam; 1.
DR TIGRFAMs; TIGR01126; pdi_dom; 2.
DR PROSITE; PS00014; ER_TARGET; 1.
DR PROSITE; PS00194; THIOREDOXIN_1; 2.
DR PROSITE; PS51352; THIOREDOXIN_2; 2.
PE 1: Evidence at protein level;
KW 3D-structure; Cell membrane; Chaperone; Complete proteome;
KW Direct protein sequencing; Disulfide bond; Endoplasmic reticulum;
KW Isomerase; Membrane; Redox-active center; Reference proteome; Repeat;
KW Signal.
FT SIGNAL 1 17
FT CHAIN 18 508 Protein disulfide-isomerase.
FT /FTId=PRO_0000034195.
FT DOMAIN 18 134 Thioredoxin 1.
FT DOMAIN 349 475 Thioredoxin 2.
FT MOTIF 505 508 Prevents secretion from ER.
FT ACT_SITE 53 53 Nucleophile.
FT ACT_SITE 56 56 Nucleophile.
FT ACT_SITE 397 397 Nucleophile (By similarity).
FT ACT_SITE 400 400 Nucleophile (By similarity).
FT SITE 54 54 Contributes to redox potential value.
FT SITE 55 55 Contributes to redox potential value.
FT SITE 120 120 Lowers pKa of C-terminal Cys of first
FT active site.
FT SITE 398 398 Contributes to redox potential value (By
FT similarity).
FT SITE 399 399 Contributes to redox potential value (By
FT similarity).
FT SITE 461 461 Lowers pKa of C-terminal Cys of second
FT active site (By similarity).
FT DISULFID 53 56 Redox-active.
FT DISULFID 397 400 Redox-active (By similarity).
FT CONFLICT 10 11 AV -> PW (in Ref. 1; CAA28775).
FT CONFLICT 21 21 E -> D (in Ref. 13; AA sequence).
FT CONFLICT 24 24 D -> V (in Ref. 13; AA sequence).
FT CONFLICT 44 45 LL -> PP (in Ref. 1; CAA28775).
FT CONFLICT 49 49 Y -> H (in Ref. 1; CAA28775).
FT CONFLICT 141 141 P -> R (in Ref. 2; AAA61169).
FT CONFLICT 360 362 LPE -> RAG (in Ref. 2; AAA61169).
FT CONFLICT 372 372 L -> P (in Ref. 2; AAA61169).
FT CONFLICT 439 439 S -> G (in Ref. 1; CAA28775).
FT CONFLICT 444 444 K -> G (in Ref. 1; CAA28775).
FT CONFLICT 460 460 E -> Q (in Ref. 15; CAA30112).
FT CONFLICT 481 481 D -> V (in Ref. 1; CAA28775).
FT STRAND 21 23
FT STRAND 26 28
FT TURN 31 33
FT HELIX 34 40
FT STRAND 42 49
FT HELIX 54 72
FT STRAND 78 83
FT TURN 84 86
FT HELIX 88 93
FT STRAND 101 106
FT STRAND 110 112
FT STRAND 114 116
FT HELIX 122 132
FT STRAND 137 139
FT HELIX 143 151
FT STRAND 153 160
FT TURN 162 165
FT HELIX 167 178
FT STRAND 180 182
FT STRAND 184 187
FT HELIX 190 195
FT STRAND 199 209
FT STRAND 212 215
FT HELIX 222 232
FT STRAND 237 239
FT TURN 242 244
FT HELIX 245 249
FT STRAND 250 252
FT STRAND 255 260
FT STRAND 265 267
FT HELIX 268 280
FT TURN 281 285
FT STRAND 287 291
FT HELIX 296 298
FT HELIX 299 304
FT HELIX 309 311
FT STRAND 313 319
FT STRAND 321 323
FT STRAND 325 327
FT STRAND 330 332
FT HELIX 336 347
FT STRAND 353 355
FT HELIX 362 364
FT STRAND 367 372
FT TURN 374 376
FT HELIX 377 381
FT STRAND 387 393
FT HELIX 398 413
FT TURN 414 416
FT STRAND 418 426
FT TURN 427 429
FT STRAND 439 446
FT STRAND 448 451
FT HELIX 463 470
FT TURN 471 473
SQ SEQUENCE 508 AA; 57116 MW; 906CE6D9900B8FCE CRC64;
MLRRALLCLA VAALVRADAP EEEDHVLVLR KSNFAEALAA HKYLLVEFYA PWCGHCKALA
PEYAKAAGKL KAEGSEIRLA KVDATEESDL AQQYGVRGYP TIKFFRNGDT ASPKEYTAGR
EADDIVNWLK KRTGPAATTL PDGAAAESLV ESSEVAVIGF FKDVESDSAK QFLQAAEAID
DIPFGITSNS DVFSKYQLDK DGVVLFKKFD EGRNNFEGEV TKENLLDFIK HNQLPLVIEF
TEQTAPKIFG GEIKTHILLF LPKSVSDYDG KLSNFKTAAE SFKGKILFIF IDSDHTDNQR
ILEFFGLKKE ECPAVRLITL EEEMTKYKPE SEELTAERIT EFCHRFLEGK IKPHLMSQEL
PEDWDKQPVK VLVGKNFEDV AFDEKKNVFV EFYAPWCGHC KQLAPIWDKL GETYKDHENI
VIAKMDSTAN EVEAVKVHSF PTLKFFPASA DRTVIDYNGE RTLDGFKKFL ESGGQDGAGD
DDDLEDLEEA EEPDMEEDDD QKAVKDEL
//
ID PDIA1_HUMAN Reviewed; 508 AA.
AC P07237; B2RDQ2; P30037; P32079; Q15205; Q6LDE5;
DT 01-APR-1988, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-NOV-1997, sequence version 3.
DT 22-JAN-2014, entry version 187.
DE RecName: Full=Protein disulfide-isomerase;
DE Short=PDI;
DE EC=5.3.4.1;
DE AltName: Full=Cellular thyroid hormone-binding protein;
DE AltName: Full=Prolyl 4-hydroxylase subunit beta;
DE AltName: Full=p55;
DE Flags: Precursor;
GN Name=P4HB; Synonyms=ERBA2L, PDI, PDIA1, PO4DB;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=3034602;
RA Pihlajaniemi T., Helaakoski T., Tasanen K., Myllylae R.,
RA Huhtala M.-L., Koivu J., Kivirikko K.I.;
RT "Molecular cloning of the beta-subunit of human prolyl 4-hydroxylase.
RT This subunit and protein disulphide isomerase are products of the same
RT gene.";
RL EMBO J. 6:643-649(1987).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=3611107;
RA Cheng S.-Y., Gong Q.-H., Parkison C., Robinson E.A., Appella E.,
RA Merlino G.T., Pastan I.;
RT "The nucleotide sequence of a human cellular thyroid hormone binding
RT protein present in endoplasmic reticulum.";
RL J. Biol. Chem. 262:11221-11227(1987).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC TISSUE=Blood;
RX PubMed=2846539;
RA Tasanen K., Parkkonen T., Chow L.T., Kivirikko K.I., Pihlajaniemi T.;
RT "Characterization of the human gene for a polypeptide that acts both
RT as the beta subunit of prolyl 4-hydroxylase and as protein disulfide
RT isomerase.";
RL J. Biol. Chem. 263:16218-16224(1988).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Synovium;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Colon, Lung, and Skin;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [7]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-24.
RX PubMed=1597478;
RA Tasanen K., Oikarinen J., Kivirikko K.I., Pihlajaniemi T.;
RT "Promoter of the gene for the multifunctional protein disulfide
RT isomerase polypeptide. Functional significance of the six CCAAT boxes
RT and other promoter elements.";
RL J. Biol. Chem. 267:11513-11519(1992).
RN [8]
RP PROTEIN SEQUENCE OF 18-41.
RC TISSUE=Colon carcinoma;
RX PubMed=9150948; DOI=10.1002/elps.1150180344;
RA Ji H., Reid G.E., Moritz R.L., Eddes J.S., Burgess A.W., Simpson R.J.;
RT "A two-dimensional gel database of human colon carcinoma proteins.";
RL Electrophoresis 18:605-613(1997).
RN [9]
RP PROTEIN SEQUENCE OF 18-30.
RC TISSUE=Platelet;
RX PubMed=12665801; DOI=10.1038/nbt810;
RA Gevaert K., Goethals M., Martens L., Van Damme J., Staes A.,
RA Thomas G.R., Vandekerckhove J.;
RT "Exploring proteomes and analyzing protein processing by mass
RT spectrometric identification of sorted N-terminal peptides.";
RL Nat. Biotechnol. 21:566-569(2003).
RN [10]
RP PROTEIN SEQUENCE OF 18-29.
RC TISSUE=Liver;
RA Frutiger S., Hughes G.J.;
RL Submitted (FEB-1996) to UniProtKB.
RN [11]
RP PROTEIN SEQUENCE OF 18-26.
RX PubMed=2079031; DOI=10.1002/elps.1150111019;
RA Ward L.D., Hong J., Whitehead R.H., Simpson R.J.;
RT "Development of a database of amino acid sequences for human colon
RT carcinoma proteins separated by two-dimensional polyacrylamide gel
RT electrophoresis.";
RL Electrophoresis 11:883-891(1990).
RN [12]
RP PRELIMINARY PROTEIN SEQUENCE OF 19-28.
RC TISSUE=Liver;
RX PubMed=1286669; DOI=10.1002/elps.11501301201;
RA Hochstrasser D.F., Frutiger S., Paquet N., Bairoch A., Ravier F.,
RA Pasquali C., Sanchez J.-C., Tissot J.-D., Bjellqvist B., Vargas R.,
RA Appel R.D., Hughes G.J.;
RT "Human liver protein map: a reference database established by
RT microsequencing and gel comparison.";
RL Electrophoresis 13:992-1001(1992).
RN [13]
RP PROTEIN SEQUENCE OF 19-28.
RX PubMed=9399589;
RA Urade R., Oda T., Ito H., Moriyama T., Utsumi S., Kito M.;
RT "Functions of characteristic Cys-Gly-His-Cys (CGHC) and Gln-Glu-Asp-
RT Leu (QEDL) motifs of microsomal ER-60 protease.";
RL J. Biochem. 122:834-842(1997).
RN [14]
RP PROTEIN SEQUENCE OF 201-207; 223-230; 286-308 AND 402-409, AND MASS
RP SPECTROMETRY.
RC TISSUE=Brain, Cajal-Retzius cell, and Fetal brain cortex;
RA Lubec G., Vishwanath V., Chen W.-Q., Sun Y.;
RL Submitted (DEC-2008) to UniProtKB.
RN [15]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 293-508.
RX PubMed=3342239; DOI=10.1016/0167-4781(88)90080-2;
RA Morris J.I., Varandani P.T.;
RT "Characterization of a cDNA for human glutathione-insulin
RT transhydrogenase (protein-disulfide isomerase/oxidoreductase).";
RL Biochim. Biophys. Acta 949:169-180(1988).
RN [16]
RP PROTEIN SEQUENCE OF 317-325; 350-369 AND 401-419.
RX PubMed=1699755; DOI=10.1002/elps.1150110703;
RA Bauw G., Rasmussen H.H., van den Bulcke M., van Damme J., Puype M.,
RA Gesser B., Celis J.E., Vandekerckhove J.;
RT "Two-dimensional gel electrophoresis, protein electroblotting and
RT microsequencing: a direct link between proteins and genes.";
RL Electrophoresis 11:528-536(1990).
RN [17]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=10636893; DOI=10.1074/jbc.275.3.1920;
RA Mezghrani A., Courageot J., Mani J.-C., Pugniere M., Bastiani P.,
RA Miquelis R.;
RT "Protein-disulfide isomerase (PDI) in FRTL5 cells. pH-dependent
RT thyroglobulin/PDI interactions determine a novel PDI function in the
RT post-endoplasmic reticulum of thyrocytes.";
RL J. Biol. Chem. 275:1920-1929(2000).
RN [18]
RP REDUCTION OF HIV-1 SURFACE PROTEIN GP120 DISULFIDE BONDS, AND
RP SUBCELLULAR LOCATION.
RX PubMed=11181151; DOI=10.1086/318823;
RA Fenouillet E., Barbouche R., Courageot J., Miquelis R.;
RT "The catalytic activity of protein disulfide isomerase is involved in
RT human immunodeficiency virus envelope-mediated membrane fusion after
RT CD4 cell binding.";
RL J. Infect. Dis. 183:744-752(2001).
RN [19]
RP FUNCTION.
RX PubMed=12485997; DOI=10.1093/emboj/cdf685;
RA Lumb R.A., Bulleid N.J.;
RT "Is protein disulfide isomerase a redox-dependent molecular
RT chaperone?";
RL EMBO J. 21:6763-6770(2002).
RN [20]
RP INTERACTION WITH UBQLN1.
RX PubMed=12095988; DOI=10.1074/jbc.M203412200;
RA Ko H.S., Uehara T., Nomura Y.;
RT "Role of ubiquilin associated with protein-disulfide isomerase in the
RT endoplasmic reticulum in stress-induced apoptotic cell death.";
RL J. Biol. Chem. 277:35386-35392(2002).
RN [21]
RP REDUCTION OF HIV-1 SURFACE PROTEIN GP120 DISULFIDE BONDS.
RX PubMed=12218051; DOI=10.1074/jbc.M204547200;
RA Gallina A., Hanley T.M., Mandel R., Trahey M., Broder C.C.,
RA Viglianti G.A., Ryser H.J.;
RT "Inhibitors of protein-disulfide isomerase prevent cleavage of
RT disulfide bonds in receptor-bound glycoprotein 120 and prevent HIV-1
RT entry.";
RL J. Biol. Chem. 277:50579-50588(2002).
RN [22]
RP REDUCTION OF HIV-1 SURFACE PROTEIN GP120 DISULFIDE BONDS.
RX PubMed=12218052; DOI=10.1074/jbc.M205467200;
RA Barbouche R., Miquelis R., Jones I.M., Fenouillet E.;
RT "Protein-disulfide isomerase-mediated reduction of two disulfide bonds
RT of HIV envelope glycoprotein 120 occurs post-CXCR4 binding and is
RT required for fusion.";
RL J. Biol. Chem. 278:3131-3136(2003).
RN [23]
RP SUBCELLULAR LOCATION [LARGE SCALE ANALYSIS], AND MASS SPECTROMETRY.
RC TISSUE=Melanoma;
RX PubMed=12643545; DOI=10.1021/pr025562r;
RA Basrur V., Yang F., Kushimoto T., Higashimoto Y., Yasumoto K.,
RA Valencia J., Muller J., Vieira W.D., Watabe H., Shabanowitz J.,
RA Hearing V.J., Hunt D.F., Appella E.;
RT "Proteomic analysis of early melanosomes: identification of novel
RT melanosomal proteins.";
RL J. Proteome Res. 2:69-79(2003).
RN [24]
RP REVIEW.
RX PubMed=15158710; DOI=10.1016/j.bbapap.2004.02.017;
RA Wilkinson B., Gilbert H.F.;
RT "Protein disulfide isomerase.";
RL Biochim. Biophys. Acta 1699:35-44(2004).
RN [25]
RP REDUCTION OF HIV-1 SURFACE PROTEIN GP120 DISULFIDE BONDS.
RX PubMed=14592831; DOI=10.1182/blood-2003-05-1390;
RA Markovic I., Stantchev T.S., Fields K.H., Tiffany L.J., Tomic M.,
RA Weiss C.D., Broder C.C., Strebel K., Clouse K.A.;
RT "Thiol/disulfide exchange is a prerequisite for CXCR4-tropic HIV-1
RT envelope-mediated T-cell fusion during viral entry.";
RL Blood 103:1586-1594(2004).
RN [26]
RP REDUCTION OF HIV-1 SURFACE PROTEIN GP120 DISULFIDE BONDS.
RX PubMed=15644496; DOI=10.1124/mol.104.008276;
RA Barbouche R., Lortat-Jacob H., Jones I.M., Fenouillet E.;
RT "Glycosaminoglycans and protein disulfide isomerase-mediated reduction
RT of HIV Env.";
RL Mol. Pharmacol. 67:1111-1118(2005).
RN [27]
RP SUBCELLULAR LOCATION [LARGE SCALE ANALYSIS], AND MASS SPECTROMETRY.
RC TISSUE=Melanoma;
RX PubMed=17081065; DOI=10.1021/pr060363j;
RA Chi A., Valencia J.C., Hu Z.-Z., Watabe H., Yamaguchi H.,
RA Mangini N.J., Huang H., Canfield V.A., Cheng K.C., Yang F., Abe R.,
RA Yamagishi S., Shabanowitz J., Hearing V.J., Wu C., Appella E.,
RA Hunt D.F.;
RT "Proteomic and bioinformatic characterization of the biogenesis and
RT function of melanosomes.";
RL J. Proteome Res. 5:3135-3144(2006).
RN [28]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [29]
RP STRUCTURE BY NMR OF 18-137.
RX PubMed=8580850;
RA Kemmink J., Darby N.J., Dijkstra K., Scheek R.M., Creighton T.E.;
RT "Nuclear magnetic resonance characterization of the N-terminal
RT thioredoxin-like domain of protein disulfide isomerase.";
RL Protein Sci. 4:2587-2593(1995).
RN [30]
RP STRUCTURE BY NMR OF 18-137, AND DISULFIDE BOND.
RX PubMed=8672469; DOI=10.1021/bi960335m;
RA Kemmink J., Darby N.J., Dijkstra K., Nilges M., Creighton T.E.;
RT "Structure determination of the N-terminal thioredoxin-like domain of
RT protein disulfide isomerase using multidimensional heteronuclear
RT 13C/15N NMR spectroscopy.";
RL Biochemistry 35:7684-7691(1996).
RN [31]
RP STRUCTURE BY NMR OF 136-245.
RX PubMed=10383197; DOI=10.1023/A:1008341820489;
RA Kemmink J., Dijkstra K., Mariani M., Scheek R.M., Penka E., Nilges M.,
RA Darby N.J.;
RT "The structure in solution of the B domain of protein disulfide
RT isomerase.";
RL J. Biomol. NMR 13:357-368(1999).
RN [32]
RP STRUCTURE BY NMR OF 368-477.
RG RIKEN structural genomics initiative (RSGI);
RT "The solution structure of the second thioredoxin-like domain of human
RT protein disulfide-isomerase.";
RL Submitted (NOV-2005) to the PDB data bank.
CC -!- FUNCTION: This multifunctional protein catalyzes the formation,
CC breakage and rearrangement of disulfide bonds. At the cell
CC surface, seems to act as a reductase that cleaves disulfide bonds
CC of proteins attached to the cell. May therefore cause structural
CC modifications of exofacial proteins. Inside the cell, seems to
CC form/rearrange disulfide bonds of nascent proteins. At high
CC concentrations, functions as a chaperone that inhibits aggregation
CC of misfolded proteins. At low concentrations, facilitates
CC aggregation (anti-chaperone activity). May be involved with other
CC chaperones in the structural modification of the TG precursor in
CC hormone biogenesis. Also acts a structural subunit of various
CC enzymes such as prolyl 4-hydroxylase and microsomal
CC triacylglycerol transfer protein MTTP.
CC -!- CATALYTIC ACTIVITY: Catalyzes the rearrangement of -S-S- bonds in
CC proteins.
CC -!- SUBUNIT: Homodimer. Monomers and homotetramers may also occur.
CC Also constitutes the structural subunit of prolyl 4-hydroxylase
CC and of the microsomal triacylglycerol transfer protein MTTP in
CC mammalian cells. Stabilizes both enzymes and retain them in the ER
CC without contributing to the catalytic activity (By similarity).
CC Binds UBQLN1. Binds to CD4, and upon HIV-1 binding to the cell
CC membrane, is part of a P4HB/PDI-CD4-CXCR4-gp120 complex.
CC -!- INTERACTION:
CC Q96HE7:ERO1L; NbExp=2; IntAct=EBI-395883, EBI-2564539;
CC Q8TCT9:HM13; NbExp=3; IntAct=EBI-395883, EBI-347472;
CC Q13162:PRDX4; NbExp=2; IntAct=EBI-395883, EBI-2211957;
CC Q03518:TAP1; NbExp=4; IntAct=EBI-395883, EBI-747259;
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum lumen. Melanosome.
CC Cell membrane; Peripheral membrane protein (Potential).
CC Note=Highly abundant. In some cell types, seems to be also
CC secreted or associated with the plasma membrane, where it
CC undergoes constant shedding and replacement from intracellular
CC sources (Probable). Localizes near CD4-enriched regions on
CC lymphoid cell surfaces. Identified by mass spectrometry in
CC melanosome fractions from stage I to stage IV.
CC -!- MISCELLANEOUS: Reduces and may activate fusogenic properties of
CC HIV-1 gp120 surface protein, thereby enabling HIV-1 entry into the
CC cell.
CC -!- SIMILARITY: Belongs to the protein disulfide isomerase family.
CC -!- SIMILARITY: Contains 2 thioredoxin domains.
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DR EMBL; X05130; CAA28775.1; -; mRNA.
DR EMBL; J02783; AAA61169.1; -; mRNA.
DR EMBL; M22806; AAC13652.1; -; Genomic_DNA.
DR EMBL; M22803; AAC13652.1; JOINED; Genomic_DNA.
DR EMBL; M22804; AAC13652.1; JOINED; Genomic_DNA.
DR EMBL; M22805; AAC13652.1; JOINED; Genomic_DNA.
DR EMBL; AK315631; BAG37999.1; -; mRNA.
DR EMBL; CH471099; EAW89690.1; -; Genomic_DNA.
DR EMBL; BC010859; AAH10859.1; -; mRNA.
DR EMBL; BC029617; AAH29617.1; -; mRNA.
DR EMBL; BC071892; AAH71892.1; -; mRNA.
DR EMBL; S37207; AAB22262.2; -; Genomic_DNA.
DR EMBL; X07077; CAA30112.1; -; mRNA.
DR PIR; A31913; ISHUSS.
DR RefSeq; NP_000909.2; NM_000918.3.
DR UniGene; Hs.464336; -.
DR PDB; 1BJX; NMR; -; A=136-245.
DR PDB; 1MEK; NMR; -; A=18-137.
DR PDB; 1X5C; NMR; -; A=368-475.
DR PDB; 2BJX; NMR; -; A=136-245.
DR PDB; 2K18; NMR; -; A=135-357.
DR PDB; 3BJ5; X-ray; 2.20 A; A=230-368.
DR PDB; 3UEM; X-ray; 2.29 A; A=137-479.
DR PDB; 4EKZ; X-ray; 2.51 A; A=18-479.
DR PDB; 4EL1; X-ray; 2.88 A; A/B=18-479.
DR PDBsum; 1BJX; -.
DR PDBsum; 1MEK; -.
DR PDBsum; 1X5C; -.
DR PDBsum; 2BJX; -.
DR PDBsum; 2K18; -.
DR PDBsum; 3BJ5; -.
DR PDBsum; 3UEM; -.
DR PDBsum; 4EKZ; -.
DR PDBsum; 4EL1; -.
DR ProteinModelPortal; P07237; -.
DR SMR; P07237; 17-478.
DR IntAct; P07237; 29.
DR MINT; MINT-4999403; -.
DR STRING; 9606.ENSP00000327801; -.
DR BindingDB; P07237; -.
DR ChEMBL; CHEMBL2364681; -.
DR PhosphoSite; P07237; -.
DR DMDM; 2507460; -.
DR DOSAC-COBS-2DPAGE; P07237; -.
DR OGP; P07237; -.
DR REPRODUCTION-2DPAGE; IPI00010796; -.
DR REPRODUCTION-2DPAGE; P07237; -.
DR SWISS-2DPAGE; P07237; -.
DR PaxDb; P07237; -.
DR PeptideAtlas; P07237; -.
DR PRIDE; P07237; -.
DR DNASU; 5034; -.
DR Ensembl; ENST00000331483; ENSP00000327801; ENSG00000185624.
DR GeneID; 5034; -.
DR KEGG; hsa:5034; -.
DR UCSC; uc002kbn.1; human.
DR CTD; 5034; -.
DR GeneCards; GC17M079801; -.
DR HGNC; HGNC:8548; P4HB.
DR HPA; CAB012463; -.
DR HPA; HPA018884; -.
DR MIM; 176790; gene.
DR neXtProt; NX_P07237; -.
DR PharmGKB; PA32876; -.
DR eggNOG; COG0526; -.
DR HOGENOM; HOG000162459; -.
DR HOVERGEN; HBG005920; -.
DR InParanoid; P07237; -.
DR KO; K09580; -.
DR OMA; KSHILMF; -.
DR OrthoDB; EOG7VHSX1; -.
DR PhylomeDB; P07237; -.
DR BRENDA; 5.3.4.1; 2681.
DR Reactome; REACT_111217; Metabolism.
DR Reactome; REACT_118779; Extracellular matrix organization.
DR ChiTaRS; P4HB; human.
DR EvolutionaryTrace; P07237; -.
DR GeneWiki; P4HB; -.
DR GenomeRNAi; 5034; -.
DR NextBio; 19398; -.
DR PMAP-CutDB; P07237; -.
DR PRO; PR:P07237; -.
DR ArrayExpress; P07237; -.
DR Bgee; P07237; -.
DR CleanEx; HS_P4HB; -.
DR Genevestigator; P07237; -.
DR GO; GO:0009986; C:cell surface; IDA:UniProtKB.
DR GO; GO:0005788; C:endoplasmic reticulum lumen; TAS:Reactome.
DR GO; GO:0005793; C:endoplasmic reticulum-Golgi intermediate compartment; IDA:UniProtKB.
DR GO; GO:0005576; C:extracellular region; NAS:UniProtKB.
DR GO; GO:0042470; C:melanosome; IEA:UniProtKB-SubCell.
DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0004656; F:procollagen-proline 4-dioxygenase activity; IDA:MGI.
DR GO; GO:0003756; F:protein disulfide isomerase activity; TAS:ProtInc.
DR GO; GO:0015035; F:protein disulfide oxidoreductase activity; IEA:InterPro.
DR GO; GO:0045454; P:cell redox homeostasis; IEA:InterPro.
DR GO; GO:0071456; P:cellular response to hypoxia; IMP:BHF-UCL.
DR GO; GO:0030198; P:extracellular matrix organization; TAS:Reactome.
DR GO; GO:0006662; P:glycerol ether metabolic process; IEA:InterPro.
DR GO; GO:0042157; P:lipoprotein metabolic process; TAS:Reactome.
DR GO; GO:0018401; P:peptidyl-proline hydroxylation to 4-hydroxy-L-proline; IDA:MGI.
DR GO; GO:1902175; P:regulation of intrinsic apoptotic signaling pathway in response to oxidative stress; IMP:BHF-UCL.
DR GO; GO:0034976; P:response to endoplasmic reticulum stress; IMP:BHF-UCL.
DR Gene3D; 3.40.30.10; -; 4.
DR InterPro; IPR005788; Disulphide_isomerase.
DR InterPro; IPR005792; Prot_disulphide_isomerase.
DR InterPro; IPR005746; Thioredoxin.
DR InterPro; IPR012336; Thioredoxin-like_fold.
DR InterPro; IPR017937; Thioredoxin_CS.
DR InterPro; IPR013766; Thioredoxin_domain.
DR Pfam; PF00085; Thioredoxin; 2.
DR PRINTS; PR00421; THIOREDOXIN.
DR SUPFAM; SSF52833; SSF52833; 4.
DR TIGRFAMs; TIGR01130; ER_PDI_fam; 1.
DR TIGRFAMs; TIGR01126; pdi_dom; 2.
DR PROSITE; PS00014; ER_TARGET; 1.
DR PROSITE; PS00194; THIOREDOXIN_1; 2.
DR PROSITE; PS51352; THIOREDOXIN_2; 2.
PE 1: Evidence at protein level;
KW 3D-structure; Cell membrane; Chaperone; Complete proteome;
KW Direct protein sequencing; Disulfide bond; Endoplasmic reticulum;
KW Isomerase; Membrane; Redox-active center; Reference proteome; Repeat;
KW Signal.
FT SIGNAL 1 17
FT CHAIN 18 508 Protein disulfide-isomerase.
FT /FTId=PRO_0000034195.
FT DOMAIN 18 134 Thioredoxin 1.
FT DOMAIN 349 475 Thioredoxin 2.
FT MOTIF 505 508 Prevents secretion from ER.
FT ACT_SITE 53 53 Nucleophile.
FT ACT_SITE 56 56 Nucleophile.
FT ACT_SITE 397 397 Nucleophile (By similarity).
FT ACT_SITE 400 400 Nucleophile (By similarity).
FT SITE 54 54 Contributes to redox potential value.
FT SITE 55 55 Contributes to redox potential value.
FT SITE 120 120 Lowers pKa of C-terminal Cys of first
FT active site.
FT SITE 398 398 Contributes to redox potential value (By
FT similarity).
FT SITE 399 399 Contributes to redox potential value (By
FT similarity).
FT SITE 461 461 Lowers pKa of C-terminal Cys of second
FT active site (By similarity).
FT DISULFID 53 56 Redox-active.
FT DISULFID 397 400 Redox-active (By similarity).
FT CONFLICT 10 11 AV -> PW (in Ref. 1; CAA28775).
FT CONFLICT 21 21 E -> D (in Ref. 13; AA sequence).
FT CONFLICT 24 24 D -> V (in Ref. 13; AA sequence).
FT CONFLICT 44 45 LL -> PP (in Ref. 1; CAA28775).
FT CONFLICT 49 49 Y -> H (in Ref. 1; CAA28775).
FT CONFLICT 141 141 P -> R (in Ref. 2; AAA61169).
FT CONFLICT 360 362 LPE -> RAG (in Ref. 2; AAA61169).
FT CONFLICT 372 372 L -> P (in Ref. 2; AAA61169).
FT CONFLICT 439 439 S -> G (in Ref. 1; CAA28775).
FT CONFLICT 444 444 K -> G (in Ref. 1; CAA28775).
FT CONFLICT 460 460 E -> Q (in Ref. 15; CAA30112).
FT CONFLICT 481 481 D -> V (in Ref. 1; CAA28775).
FT STRAND 21 23
FT STRAND 26 28
FT TURN 31 33
FT HELIX 34 40
FT STRAND 42 49
FT HELIX 54 72
FT STRAND 78 83
FT TURN 84 86
FT HELIX 88 93
FT STRAND 101 106
FT STRAND 110 112
FT STRAND 114 116
FT HELIX 122 132
FT STRAND 137 139
FT HELIX 143 151
FT STRAND 153 160
FT TURN 162 165
FT HELIX 167 178
FT STRAND 180 182
FT STRAND 184 187
FT HELIX 190 195
FT STRAND 199 209
FT STRAND 212 215
FT HELIX 222 232
FT STRAND 237 239
FT TURN 242 244
FT HELIX 245 249
FT STRAND 250 252
FT STRAND 255 260
FT STRAND 265 267
FT HELIX 268 280
FT TURN 281 285
FT STRAND 287 291
FT HELIX 296 298
FT HELIX 299 304
FT HELIX 309 311
FT STRAND 313 319
FT STRAND 321 323
FT STRAND 325 327
FT STRAND 330 332
FT HELIX 336 347
FT STRAND 353 355
FT HELIX 362 364
FT STRAND 367 372
FT TURN 374 376
FT HELIX 377 381
FT STRAND 387 393
FT HELIX 398 413
FT TURN 414 416
FT STRAND 418 426
FT TURN 427 429
FT STRAND 439 446
FT STRAND 448 451
FT HELIX 463 470
FT TURN 471 473
SQ SEQUENCE 508 AA; 57116 MW; 906CE6D9900B8FCE CRC64;
MLRRALLCLA VAALVRADAP EEEDHVLVLR KSNFAEALAA HKYLLVEFYA PWCGHCKALA
PEYAKAAGKL KAEGSEIRLA KVDATEESDL AQQYGVRGYP TIKFFRNGDT ASPKEYTAGR
EADDIVNWLK KRTGPAATTL PDGAAAESLV ESSEVAVIGF FKDVESDSAK QFLQAAEAID
DIPFGITSNS DVFSKYQLDK DGVVLFKKFD EGRNNFEGEV TKENLLDFIK HNQLPLVIEF
TEQTAPKIFG GEIKTHILLF LPKSVSDYDG KLSNFKTAAE SFKGKILFIF IDSDHTDNQR
ILEFFGLKKE ECPAVRLITL EEEMTKYKPE SEELTAERIT EFCHRFLEGK IKPHLMSQEL
PEDWDKQPVK VLVGKNFEDV AFDEKKNVFV EFYAPWCGHC KQLAPIWDKL GETYKDHENI
VIAKMDSTAN EVEAVKVHSF PTLKFFPASA DRTVIDYNGE RTLDGFKKFL ESGGQDGAGD
DDDLEDLEEA EEPDMEEDDD QKAVKDEL
//
MIM
176790
*RECORD*
*FIELD* NO
176790
*FIELD* TI
*176790 PROCOLLAGEN-PROLINE, 2-OXOGLUTARATE-4-DIOXYGENASE, BETA SUBUNIT; P4HB
;;PROLYL 4-HYDROXYLASE, BETA SUBUNIT;;
read morePHDB; PROHB; PO4HB;;
DISULFIDE ISOMERASE; DSI;;
PROTEIN DISULFIDE ISOMERASE/OXIDOREDUCTASE; PDI;;
PROTEIN DISULFIDE ISOMERASE, FAMILY A, MEMBER 1; PDIA1;;
THYROID HORMONE-BINDING PROTEIN p55, CELLULAR;;
GLUTATHIONE-INSULIN TRANSHYDROGENASE; GIT
*FIELD* TX
CLONING
Prolyl 4-hydroxylase (EC 1.14.11.2) is involved in hydroxylation of
prolyl residues in preprocollagen. Pihlajaniemi et al. (1987) cloned the
PROHB gene. Prolyl 4-hydroxylase is a tetramer consisting of 2 alpha
(176710, 600608) and 2 beta subunits of molecular weights about 64,000
and 60,000, respectively, for the monomers. Characterization of cDNA
clones for the human beta subunit indicated that the polypeptide is 508
amino acids long, including a signal peptide of 17 amino acids.
Pihlajaniemi et al. (1987) also found that disulfide isomerase (EC
5.3.4.1) is a product of the same gene. When present in cells in
monomeric form, the protein serves the function of DSI (Koivu et al.,
1987); when present in the prolyl 4-hydroxylase tetramer, it catalyzes
the formation of 4-hydroxyproline in collagen.
Cheng et al. (1987) demonstrated by molecular cloning and nucleotide
sequencing that cellular thyroid hormone-binding protein is also
identical to the beta subunit of prolyl 4-hydroxylase and protein
disulfide isomerase.
The protein disulfide isomerase/oxidoreductase (EC 1.8.4.2) is the same
enzyme molecule as P4HB (Noiva and Lennarz, 1992). Also known as
glutathione-insulin transhydrogenase, it catalyzes
thiol:protein-disulfide interchange. GSH-insulin transhydrogenase is a
ubiquitous, abundant protein that is located primarily in endoplasmic
reticulum (ER), but is also associated with plasma membrane and other
intracellular membrane compartments. Morris and Varandani (1988)
determined the nucleotide sequence of a cDNA isolated from a human liver
cDNA expression library in lambda phage gt11 with monoclonal antibodies
to rat liver protein disulfide isomerase/oxidoreductase. The largest
cDNA contained approximately 1,500 basepairs and represented an
estimated 65% of the message. They found 100% identity with rat enzyme
in the active site region and 81% similarity in other regions.
GENE STRUCTURE
Tasanen et al. (1988) isolated genomic clones for the human gene coding
for this multifunctional protein. They found that the gene is about 18
kb long and consists of 11 exons. The codons for the 2 presumed active
sites of protein disulfide isomerase, each a cys-gly-his-cys sequence,
were found to be located 12 bp from the beginning of exons 2 and 9.
MAPPING
The P4HB gene was tentatively mapped to chromosome 7 by somatic cell
hybridization (Pajunen et al., 1985). Pajunen et al. (1987, 1988)
definitively assigned the gene for the beta subunit to chromosome 17,
specifically, 17q23-q25. The identification in cell hybrids was
performed by 3 different methods: immunoblotting using species-specific
monoclonal antibodies, radioimmunoassay with species-specific polyclonal
antibodies, and Southern blot analysis using cDNA for the human beta
subunit.
The sequence of the cellular thyroid hormone-binding protein with a
molecular weight of 55,000 (p55) indicates that it is identical to
protein disulfide isomerase and the beta subunit of prolyl
4-hydroxylase. By in situ hybridization, using a cDNA for the human p55
gene, Popescu et al. (1988) localized the gene to 17q25. This indicated
that the p55 gene is not linked to either of the 2 other thyroid
hormone-binding protein genes, ERBA1 (190120) and ERBA2 (190160), which
are located at 17q11-q21 and 3pter-p21, respectively.
Pajunen et al. (1991) confirmed the assignment of P4HB to 17q25 by in
situ hybridization. Southern blot analysis of restricted DNA from a
chromosome-mediated gene transfer transfectant panel suggested that the
P4HB gene is located distal to the gene for thymidine kinase (TK1;
188300), either between the genes for thymidine kinase and galactokinase
(GALK1; 604313) or on the telomeric side of both these genes.
GENE FUNCTION
Another of the many functions of protein disulfide isomerase is its role
as the smaller element of the heterodimeric microsomal triglyceride
transfer protein (MTP; 157147). The unique larger subunit of this
heterodimer is mutant in patients with abetalipoproteinemia (200100).
Since chylomicrons, very low density lipoproteins, and low density
lipoproteins are absent from the plasma in abetalipoproteinemic
subjects, and since the clinical pathology of abetalipoproteinemia
results from deficiency of fat-soluble vitamins that are transported on
apoB-containing lipoproteins, Sharp et al. (1993) proposed that
inhibition of MTP may provide a specific mechanism for lowering plasma
cholesterol and triglyceride levels.
Mezghrani et al. (2001) found that PDI functioned with the
oxidoreductases ERO1L-alpha (ERO1L; 615435) and ERO1L-beta (ERO1LB;
615437) in disulfide bond formation. Overexpression of either ERO1L
protein in HeLa cells accelerated oxidative folding of murine
immunoglobulin J chain (IGJ; 147790). Immunoprecipitation analysis
revealed that PDI, but not the ERO1L proteins, formed a mixed disulfide
with IgJ during oxidative folding. PDI also formed mixed disulfides with
ERO1L-alpha and ERO1L-beta. The ERO1L proteins oxidized PDI, but not the
related oxidoreductase ERP57 (PDIA3; 602046). PDI was not oxidized by
mutant ERO1L-alpha containing alanine substitutions of cys394 or cys397
within a critical CxxCxxC motif. Mezghrani et al. (2001) concluded that
PDI transfers electrons from nascent cargo proteins to ERO1L recipients
during oxidative protein folding.
PDI has 2 domains that function as independent active sites with
homology to the small, redox-active protein thioredoxin (187700). During
neurodegenerative disorders and cerebral ischemia, the accumulation of
immature and denatured proteins results in ER dysfunction, but the
upregulation of PDI represents an adaptive response to protect Uehara et
al. (2006) demonstrated, in brains manifesting sporadic Parkinson (see
168601) or Alzheimer (see 104300) disease, that PDI is S-nitrosylated, a
reaction NO-induced S-nitrosylation of PDI inhibits its enzymatic
activity, leads to the accumulation of polyubiquitinated proteins, and
activates the unfolded protein response. S-nitrosylation also abrogates
PDI-mediated attenuation of neuronal cell death triggered by ER stress,
misfolded proteins, or proteasome inhibition. Thus, Uehara et al. (2006)
concluded that PDI prevents neurotoxicity associated with ER stress and
protein misfolding, but NO blocks this protective effect in
neurodegenerative disorders through the S-nitrosylation of PDI.
Qi et al. (2008) reported physical interactions between Ago2 (606229)
and the alpha (P4H-alpha-1) (P4HA1; 176710), and beta (P4H-beta, P4HB)
subunits of the type I collagen prolyl-4-hydroxylase (C-P4H-I). Mass
spectrometric analysis identified hydroxylation of the endogenous Ago2
at proline-700. In vitro, both Ago2 and Ago4 (607356) seem to be more
efficiently hydroxylated than Ago1 (606228) and Ago3 (607355) by
recombinant human C-P4H-I. Human cells depleted of P4H-alpha-1 or
P4H-beta by short hairpin RNA, and C-P4H-alpha-I-null mouse embryonic
fibroblast cells, showed reduced stability of Ago2 and impaired short
interfering RNA-programmed RISC activity. Furthermore, mutation of
proline-700 to alanine also resulted in destabilization of Ago2, thus
linking Ago2 P700 and hydroxylation at this residue to its stability
regulation. Qi et al. (2008) concluded that their findings identified
hydroxylation as a posttranslational modification important for Ago2
stability and effective RNA interference.
Using human cell lines, Mueller et al. (2008) identified several
components of a protein complex required for retrotranslocation or
dislocation of misfolded proteins from the ER lumen to the cytosol for
proteasome-dependent degradation. These included SEL1L (602329), HRD1
(SYVN1; 608046), derlin-2 (DERL2; 610304), the ATPase p97 (VCP; 601023),
PDI, BIP (HSPA5; 138120), calnexin (CANX; 114217), AUP1 (602434), UBXD8
(FAF2), UBC6E (UBE2J1), and OS9 (609677).
Using mutation analysis, Wang et al. (2011) found that the
cys-gly-his-gly active site in amino acids 352 to 462 of PDI was
required for recombinant human PDI and ERO1L-beta to reactivate
denatured and reduced RNase A (180440) in vitro.
*FIELD* RF
1. Cheng, S. Y.; Gong, Q. H.; Parkinson, C.; Robinson, E. A.; Appella,
E.; Merlino, G. T.; Pastan, I.: The nucleotide sequence of a human
cellular thyroid hormone-binding protein present in endoplasmic reticulum. J.
Biol. Chem. 262: 11221-11227, 1987.
2. Koivu, J.; Myllyla, R.; Halaakoski, T.; Pihlajaniemi, T.; Tasanen,
K.; Kivirikko, K. I.: A single polypeptide acts both as the beta
subunit of prolyl 4-hydroxylase and as a protein disulfide-isomerase. J.
Biol. Chem. 262: 6447-6449, 1987.
3. Mezghrani, A.; Fassio, A.; Benham, A.; Simmen, T.; Braakman, I.;
Sitia, R.: Manipulation of oxidative protein folding and PDI redox
state in mammalian cells. EMBO J. 20: 6288-6296, 2001.
4. Morris, J. I.; Varandani, P. T.: Characterization of a cDNA for
human glutathione-insulin transhydrogenase (protein-disulfide isomerase/oxidoreductase). Biochim.
Biophys. Acta 949: 169-180, 1988.
5. Mueller, B.; Klemm, E. J.; Spooner, E.; Claessen, J. H.; Ploegh,
H. L.: SEL1L nucleates a protein complex required for dislocation
of misfolded glycoproteins. Proc. Nat. Acad. Sci. 105: 12325-12330,
2008.
6. Noiva, R.; Lennarz, W. J.: Protein disulfide isomerase: a multifunctional
protein resident in the lumen of the endoplasmic reticulum. J. Biol.
Chem. 267: 3553-3556, 1992.
7. Pajunen, L.; Hoyhtya, M.; Tryggvason, K.; Kivirikko, K. I.; Myllyla,
R.: Species-specific antibodies in the assignment of the gene for
the beta-subunit of human prolyl 4-hydroxylase. (Abstract) Cytogenet.
Cell Genet. 40: 719 only, 1985.
8. Pajunen, L.; Jones, T. A.; Goddard, A.; Sheer, D.; Solomon, E.;
Pihlajaniemi, T.; Kivirikko, K. I.: Regional assignment of the human
gene coding for a multifunctional polypeptide (P4HB) acting as the
beta-subunit of prolyl 4-hydroxylase and the enzyme protein disulfide
isomerase to 17q25. Cytogenet. Cell Genet. 56: 165-168, 1991.
9. Pajunen, L.; Myllyla, R.; Helaakoski, T.; Pihlajaniemi, T.; Tasanen,
K.; Hoyhtya, M.; Tryggvason, K.; Solomon, E.; Kivirikko, K. I.: Assignment
of the gene coding for both the beta-subunit of prolyl 4-hydroxylase
and protein disulphide isomerase to human chromosome region 17q23-25.
(Abstract) Cytogenet. Cell Genet. 46: 674 only, 1987.
10. Pajunen, L.; Myllyla, R.; Helaakoski, T.; Pihlajaniemi, T.; Tasanen,
K.; Hoyhtya, M.; Tryggvason, K.; Solomon, E.; Kivirikko, K. I.: Assignment
of the gene coding for both the beta-subunit of prolyl 4-hydroxylase
and the enzyme disulfide isomerase to human chromosome region 17p11-qter. Cytogenet.
Cell Genet. 47: 37-41, 1988.
11. Pihlajaniemi, T.; Helaakoski, T.; Tasanen, K.; Myllyla, R.; Huhtala,
M.-L.; Koivu, J.; Kivirikko, K. I.: Molecular cloning of the beta-subunit
of human prolyl 4-hydroxylase: this subunit and protein disulphide
isomerase are products of the same gene. EMBO J. 6: 643-649, 1987.
12. Popescu, N. C.; Cheng, S.; Pastan, I.: Chromosomal localization
of the gene for a human thyroid hormone-binding protein. Am. J. Hum.
Genet. 42: 560-564, 1988.
13. Qi, H. H.; Ongusaha, P. P.; Myllyharju, J.; Cheng, D.; Pakkanen,
O.; Shi, Y.; Lee, S. W.; Peng, J.; Shi, Y.: Prolyl 4-hydroxylation
regulates Argonaute 2 stability. Nature 455: 421-424, 2008.
14. Sharp, D.; Blinderman, L.; Combs, K. A.; Kienzle, B.; Ricci, B.;
Wager-Smith, K.; Gil, C. M.; Turck, C. W.; Bouma, M.-E.; Rader, D.
J.; Aggerbeck, L. P.; Gregg, R. E.; Gordon, D. A.; Wetterau, J. R.
: Cloning and gene defects in microsomal triglyceride transfer protein
associated with abetalipoproteinaemia. Nature 365: 65-69, 1993.
15. Tasanen, K.; Parkkonen, T.; Chow, L. T.; Kivirikko, K. I.; Pihlajaniemi,
T.: Characterization of the human gene for a polypeptide that acts
both as the beta-subunit of prolyl 4-hydroxylase and as protein disulfide
isomerase. J. Biol. Chem. 263: 16218-16224, 1988.
16. Uehara, T.; Nakamura, T.; Yao, D.; Shi, Z.-Q.; Gu, Z.; Ma, Y.;
Masliah, E.; Nomura, Y.; Lipton, S. A.: S-nitrosylated protein-disulphide
isomerase links protein misfolding to neurodegeneration. Nature 441:
513-517, 2006.
17. Wang, L.; Zhu, L.; Wang, C.: The endoplasmic reticulum sulfhydryl
oxidase Ero1-beta drives efficient oxidative protein folding with
loose regulation. Biochem. J. 434: 113-121, 2011.
*FIELD* CN
Patricia A. Hartz - updated: 10/08/2013
Patricia A. Hartz - updated: 9/23/2013
Patricia A. Hartz - updated: 11/10/2009
Ada Hamosh - updated: 10/2/2008
Ada Hamosh - updated: 7/24/2006
*FIELD* CD
Victor A. McKusick: 6/2/1986
*FIELD* ED
mgross: 10/08/2013
tpirozzi: 9/24/2013
tpirozzi: 9/23/2013
mgross: 11/10/2009
alopez: 10/6/2008
terry: 10/2/2008
mgross: 6/7/2007
alopez: 7/27/2006
terry: 7/24/2006
mgross: 10/21/2004
mgross: 11/24/1999
psherman: 8/3/1999
psherman: 8/2/1999
alopez: 3/18/1999
psherman: 9/21/1998
mimadm: 2/25/1995
terry: 10/31/1994
pfoster: 9/7/1994
carol: 9/17/1993
carol: 1/15/1993
carol: 5/22/1992
*RECORD*
*FIELD* NO
176790
*FIELD* TI
*176790 PROCOLLAGEN-PROLINE, 2-OXOGLUTARATE-4-DIOXYGENASE, BETA SUBUNIT; P4HB
;;PROLYL 4-HYDROXYLASE, BETA SUBUNIT;;
read morePHDB; PROHB; PO4HB;;
DISULFIDE ISOMERASE; DSI;;
PROTEIN DISULFIDE ISOMERASE/OXIDOREDUCTASE; PDI;;
PROTEIN DISULFIDE ISOMERASE, FAMILY A, MEMBER 1; PDIA1;;
THYROID HORMONE-BINDING PROTEIN p55, CELLULAR;;
GLUTATHIONE-INSULIN TRANSHYDROGENASE; GIT
*FIELD* TX
CLONING
Prolyl 4-hydroxylase (EC 1.14.11.2) is involved in hydroxylation of
prolyl residues in preprocollagen. Pihlajaniemi et al. (1987) cloned the
PROHB gene. Prolyl 4-hydroxylase is a tetramer consisting of 2 alpha
(176710, 600608) and 2 beta subunits of molecular weights about 64,000
and 60,000, respectively, for the monomers. Characterization of cDNA
clones for the human beta subunit indicated that the polypeptide is 508
amino acids long, including a signal peptide of 17 amino acids.
Pihlajaniemi et al. (1987) also found that disulfide isomerase (EC
5.3.4.1) is a product of the same gene. When present in cells in
monomeric form, the protein serves the function of DSI (Koivu et al.,
1987); when present in the prolyl 4-hydroxylase tetramer, it catalyzes
the formation of 4-hydroxyproline in collagen.
Cheng et al. (1987) demonstrated by molecular cloning and nucleotide
sequencing that cellular thyroid hormone-binding protein is also
identical to the beta subunit of prolyl 4-hydroxylase and protein
disulfide isomerase.
The protein disulfide isomerase/oxidoreductase (EC 1.8.4.2) is the same
enzyme molecule as P4HB (Noiva and Lennarz, 1992). Also known as
glutathione-insulin transhydrogenase, it catalyzes
thiol:protein-disulfide interchange. GSH-insulin transhydrogenase is a
ubiquitous, abundant protein that is located primarily in endoplasmic
reticulum (ER), but is also associated with plasma membrane and other
intracellular membrane compartments. Morris and Varandani (1988)
determined the nucleotide sequence of a cDNA isolated from a human liver
cDNA expression library in lambda phage gt11 with monoclonal antibodies
to rat liver protein disulfide isomerase/oxidoreductase. The largest
cDNA contained approximately 1,500 basepairs and represented an
estimated 65% of the message. They found 100% identity with rat enzyme
in the active site region and 81% similarity in other regions.
GENE STRUCTURE
Tasanen et al. (1988) isolated genomic clones for the human gene coding
for this multifunctional protein. They found that the gene is about 18
kb long and consists of 11 exons. The codons for the 2 presumed active
sites of protein disulfide isomerase, each a cys-gly-his-cys sequence,
were found to be located 12 bp from the beginning of exons 2 and 9.
MAPPING
The P4HB gene was tentatively mapped to chromosome 7 by somatic cell
hybridization (Pajunen et al., 1985). Pajunen et al. (1987, 1988)
definitively assigned the gene for the beta subunit to chromosome 17,
specifically, 17q23-q25. The identification in cell hybrids was
performed by 3 different methods: immunoblotting using species-specific
monoclonal antibodies, radioimmunoassay with species-specific polyclonal
antibodies, and Southern blot analysis using cDNA for the human beta
subunit.
The sequence of the cellular thyroid hormone-binding protein with a
molecular weight of 55,000 (p55) indicates that it is identical to
protein disulfide isomerase and the beta subunit of prolyl
4-hydroxylase. By in situ hybridization, using a cDNA for the human p55
gene, Popescu et al. (1988) localized the gene to 17q25. This indicated
that the p55 gene is not linked to either of the 2 other thyroid
hormone-binding protein genes, ERBA1 (190120) and ERBA2 (190160), which
are located at 17q11-q21 and 3pter-p21, respectively.
Pajunen et al. (1991) confirmed the assignment of P4HB to 17q25 by in
situ hybridization. Southern blot analysis of restricted DNA from a
chromosome-mediated gene transfer transfectant panel suggested that the
P4HB gene is located distal to the gene for thymidine kinase (TK1;
188300), either between the genes for thymidine kinase and galactokinase
(GALK1; 604313) or on the telomeric side of both these genes.
GENE FUNCTION
Another of the many functions of protein disulfide isomerase is its role
as the smaller element of the heterodimeric microsomal triglyceride
transfer protein (MTP; 157147). The unique larger subunit of this
heterodimer is mutant in patients with abetalipoproteinemia (200100).
Since chylomicrons, very low density lipoproteins, and low density
lipoproteins are absent from the plasma in abetalipoproteinemic
subjects, and since the clinical pathology of abetalipoproteinemia
results from deficiency of fat-soluble vitamins that are transported on
apoB-containing lipoproteins, Sharp et al. (1993) proposed that
inhibition of MTP may provide a specific mechanism for lowering plasma
cholesterol and triglyceride levels.
Mezghrani et al. (2001) found that PDI functioned with the
oxidoreductases ERO1L-alpha (ERO1L; 615435) and ERO1L-beta (ERO1LB;
615437) in disulfide bond formation. Overexpression of either ERO1L
protein in HeLa cells accelerated oxidative folding of murine
immunoglobulin J chain (IGJ; 147790). Immunoprecipitation analysis
revealed that PDI, but not the ERO1L proteins, formed a mixed disulfide
with IgJ during oxidative folding. PDI also formed mixed disulfides with
ERO1L-alpha and ERO1L-beta. The ERO1L proteins oxidized PDI, but not the
related oxidoreductase ERP57 (PDIA3; 602046). PDI was not oxidized by
mutant ERO1L-alpha containing alanine substitutions of cys394 or cys397
within a critical CxxCxxC motif. Mezghrani et al. (2001) concluded that
PDI transfers electrons from nascent cargo proteins to ERO1L recipients
during oxidative protein folding.
PDI has 2 domains that function as independent active sites with
homology to the small, redox-active protein thioredoxin (187700). During
neurodegenerative disorders and cerebral ischemia, the accumulation of
immature and denatured proteins results in ER dysfunction, but the
upregulation of PDI represents an adaptive response to protect Uehara et
al. (2006) demonstrated, in brains manifesting sporadic Parkinson (see
168601) or Alzheimer (see 104300) disease, that PDI is S-nitrosylated, a
reaction NO-induced S-nitrosylation of PDI inhibits its enzymatic
activity, leads to the accumulation of polyubiquitinated proteins, and
activates the unfolded protein response. S-nitrosylation also abrogates
PDI-mediated attenuation of neuronal cell death triggered by ER stress,
misfolded proteins, or proteasome inhibition. Thus, Uehara et al. (2006)
concluded that PDI prevents neurotoxicity associated with ER stress and
protein misfolding, but NO blocks this protective effect in
neurodegenerative disorders through the S-nitrosylation of PDI.
Qi et al. (2008) reported physical interactions between Ago2 (606229)
and the alpha (P4H-alpha-1) (P4HA1; 176710), and beta (P4H-beta, P4HB)
subunits of the type I collagen prolyl-4-hydroxylase (C-P4H-I). Mass
spectrometric analysis identified hydroxylation of the endogenous Ago2
at proline-700. In vitro, both Ago2 and Ago4 (607356) seem to be more
efficiently hydroxylated than Ago1 (606228) and Ago3 (607355) by
recombinant human C-P4H-I. Human cells depleted of P4H-alpha-1 or
P4H-beta by short hairpin RNA, and C-P4H-alpha-I-null mouse embryonic
fibroblast cells, showed reduced stability of Ago2 and impaired short
interfering RNA-programmed RISC activity. Furthermore, mutation of
proline-700 to alanine also resulted in destabilization of Ago2, thus
linking Ago2 P700 and hydroxylation at this residue to its stability
regulation. Qi et al. (2008) concluded that their findings identified
hydroxylation as a posttranslational modification important for Ago2
stability and effective RNA interference.
Using human cell lines, Mueller et al. (2008) identified several
components of a protein complex required for retrotranslocation or
dislocation of misfolded proteins from the ER lumen to the cytosol for
proteasome-dependent degradation. These included SEL1L (602329), HRD1
(SYVN1; 608046), derlin-2 (DERL2; 610304), the ATPase p97 (VCP; 601023),
PDI, BIP (HSPA5; 138120), calnexin (CANX; 114217), AUP1 (602434), UBXD8
(FAF2), UBC6E (UBE2J1), and OS9 (609677).
Using mutation analysis, Wang et al. (2011) found that the
cys-gly-his-gly active site in amino acids 352 to 462 of PDI was
required for recombinant human PDI and ERO1L-beta to reactivate
denatured and reduced RNase A (180440) in vitro.
*FIELD* RF
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E.; Merlino, G. T.; Pastan, I.: The nucleotide sequence of a human
cellular thyroid hormone-binding protein present in endoplasmic reticulum. J.
Biol. Chem. 262: 11221-11227, 1987.
2. Koivu, J.; Myllyla, R.; Halaakoski, T.; Pihlajaniemi, T.; Tasanen,
K.; Kivirikko, K. I.: A single polypeptide acts both as the beta
subunit of prolyl 4-hydroxylase and as a protein disulfide-isomerase. J.
Biol. Chem. 262: 6447-6449, 1987.
3. Mezghrani, A.; Fassio, A.; Benham, A.; Simmen, T.; Braakman, I.;
Sitia, R.: Manipulation of oxidative protein folding and PDI redox
state in mammalian cells. EMBO J. 20: 6288-6296, 2001.
4. Morris, J. I.; Varandani, P. T.: Characterization of a cDNA for
human glutathione-insulin transhydrogenase (protein-disulfide isomerase/oxidoreductase). Biochim.
Biophys. Acta 949: 169-180, 1988.
5. Mueller, B.; Klemm, E. J.; Spooner, E.; Claessen, J. H.; Ploegh,
H. L.: SEL1L nucleates a protein complex required for dislocation
of misfolded glycoproteins. Proc. Nat. Acad. Sci. 105: 12325-12330,
2008.
6. Noiva, R.; Lennarz, W. J.: Protein disulfide isomerase: a multifunctional
protein resident in the lumen of the endoplasmic reticulum. J. Biol.
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7. Pajunen, L.; Hoyhtya, M.; Tryggvason, K.; Kivirikko, K. I.; Myllyla,
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Pihlajaniemi, T.; Kivirikko, K. I.: Regional assignment of the human
gene coding for a multifunctional polypeptide (P4HB) acting as the
beta-subunit of prolyl 4-hydroxylase and the enzyme protein disulfide
isomerase to 17q25. Cytogenet. Cell Genet. 56: 165-168, 1991.
9. Pajunen, L.; Myllyla, R.; Helaakoski, T.; Pihlajaniemi, T.; Tasanen,
K.; Hoyhtya, M.; Tryggvason, K.; Solomon, E.; Kivirikko, K. I.: Assignment
of the gene coding for both the beta-subunit of prolyl 4-hydroxylase
and protein disulphide isomerase to human chromosome region 17q23-25.
(Abstract) Cytogenet. Cell Genet. 46: 674 only, 1987.
10. Pajunen, L.; Myllyla, R.; Helaakoski, T.; Pihlajaniemi, T.; Tasanen,
K.; Hoyhtya, M.; Tryggvason, K.; Solomon, E.; Kivirikko, K. I.: Assignment
of the gene coding for both the beta-subunit of prolyl 4-hydroxylase
and the enzyme disulfide isomerase to human chromosome region 17p11-qter. Cytogenet.
Cell Genet. 47: 37-41, 1988.
11. Pihlajaniemi, T.; Helaakoski, T.; Tasanen, K.; Myllyla, R.; Huhtala,
M.-L.; Koivu, J.; Kivirikko, K. I.: Molecular cloning of the beta-subunit
of human prolyl 4-hydroxylase: this subunit and protein disulphide
isomerase are products of the same gene. EMBO J. 6: 643-649, 1987.
12. Popescu, N. C.; Cheng, S.; Pastan, I.: Chromosomal localization
of the gene for a human thyroid hormone-binding protein. Am. J. Hum.
Genet. 42: 560-564, 1988.
13. Qi, H. H.; Ongusaha, P. P.; Myllyharju, J.; Cheng, D.; Pakkanen,
O.; Shi, Y.; Lee, S. W.; Peng, J.; Shi, Y.: Prolyl 4-hydroxylation
regulates Argonaute 2 stability. Nature 455: 421-424, 2008.
14. Sharp, D.; Blinderman, L.; Combs, K. A.; Kienzle, B.; Ricci, B.;
Wager-Smith, K.; Gil, C. M.; Turck, C. W.; Bouma, M.-E.; Rader, D.
J.; Aggerbeck, L. P.; Gregg, R. E.; Gordon, D. A.; Wetterau, J. R.
: Cloning and gene defects in microsomal triglyceride transfer protein
associated with abetalipoproteinaemia. Nature 365: 65-69, 1993.
15. Tasanen, K.; Parkkonen, T.; Chow, L. T.; Kivirikko, K. I.; Pihlajaniemi,
T.: Characterization of the human gene for a polypeptide that acts
both as the beta-subunit of prolyl 4-hydroxylase and as protein disulfide
isomerase. J. Biol. Chem. 263: 16218-16224, 1988.
16. Uehara, T.; Nakamura, T.; Yao, D.; Shi, Z.-Q.; Gu, Z.; Ma, Y.;
Masliah, E.; Nomura, Y.; Lipton, S. A.: S-nitrosylated protein-disulphide
isomerase links protein misfolding to neurodegeneration. Nature 441:
513-517, 2006.
17. Wang, L.; Zhu, L.; Wang, C.: The endoplasmic reticulum sulfhydryl
oxidase Ero1-beta drives efficient oxidative protein folding with
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*FIELD* CN
Patricia A. Hartz - updated: 10/08/2013
Patricia A. Hartz - updated: 9/23/2013
Patricia A. Hartz - updated: 11/10/2009
Ada Hamosh - updated: 10/2/2008
Ada Hamosh - updated: 7/24/2006
*FIELD* CD
Victor A. McKusick: 6/2/1986
*FIELD* ED
mgross: 10/08/2013
tpirozzi: 9/24/2013
tpirozzi: 9/23/2013
mgross: 11/10/2009
alopez: 10/6/2008
terry: 10/2/2008
mgross: 6/7/2007
alopez: 7/27/2006
terry: 7/24/2006
mgross: 10/21/2004
mgross: 11/24/1999
psherman: 8/3/1999
psherman: 8/2/1999
alopez: 3/18/1999
psherman: 9/21/1998
mimadm: 2/25/1995
terry: 10/31/1994
pfoster: 9/7/1994
carol: 9/17/1993
carol: 1/15/1993
carol: 5/22/1992